Cannabinoid receptor modulator

ABSTRACT

A cannabinoid receptor modulator containing a compound represented by Formula (I 0 ) 
                         
wherein, X is an oxygen atom, etc., R 0  is an optionally substituted acylamino group, ring A 0  is a benzene ring which may further have a substituent in addition to R 0 , and ring B is an optionally substituted 5-membered heterocycle, or a salt thereof or a prodrug thereof.

This is a divisional of application Ser. No. 10/561,483 filed Dec. 20,2005, which is the National Stage of International Application No.PCT/JP2004/009355. The entire disclosure of the prior application,application Ser. No. 10/561,483, is hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a benzene ring-fused 5-memberedheterocyclic compound, especially a benzofuran derivative as acannabinoid receptor modulator, and a pharmaceutical compositioncontaining the same.

BACKGROUND ART

Cannabinoid receptors belong to G-protein conjugated receptor having theseven transmembraneous domain. Among these, CB1 receptor ispredominately distributed in the central nervous system, of whichexistence is known by Devane W A et al. (Molecular Pharmacology, 34,605-613 (1988)). CB2 receptor, which has a predominant cell distributionin the immune system and in the peripheral tissues, has been discoveredby Munro S et al. (Nature, 365, 61-65 (1993)). CB1 receptor and CB2receptor show 48% of homology. 97-99% amino acid sequence of CB1receptor is maintained in rat, mouse and human.

In the brain, CB1 receptor exists predominately in hippocampus,striatum, substanta nigra, basal forebrain area, olfactory bulb andcerebellum, and little in the brain stem, medulla and thalamus. CB1receptor is localized in the presynapse, and is considered to controlinhibitively the release of neurotransmitters (Trends PharmacologicalSciences, 22, 565-572 (2001)). For CB1 receptor, four kinds of agonistare well known, i.e., classic cannabinoids of tetrahydrocannabinol (THC)derivatives which are dibenzopyran rings, non-classic cannabinoids whichare bicyclic and tricyclic derivatives prepared by cleavage of the pyranrings of the THC structure, aminoalkyl indols, and arachidonic acidderivatives such as anandamide which is known as an endogenous agonist(Science, 258, 1946-1949 (1992)).

WIN55,212-2, a cannabinoid receptor agonist, has been reported toinhibit neural cell death based on cerebral ischemia (Journal ofNeuroscience, 19, 2987-2995 (1999)). The action is believed to be causedby inhibiting the release of glutamic acid through the activation of theCB1 receptor in the presynapse of glutamic acid neuron. Further,anandamide which is an endogenous ligand has been reported to showinhibitory action on neural cell death after brain injury (Nature, 413,527-531 (2001)). Further, Baker et al. have reported that WIN55,212-2,JWH-133, THC and methanandamide, which are cannabinoid receptoragonists, improved tremor or spasticity in the animal model of multiplesclerosis (Nature, 404, 84 (2000)).

Cerebrovascular disorders are the 2^(nd) or 3^(rd) leading cause ofdeath in Japan, USA and Europe, and the 1^(st) leading cause of seriousaftereffect of diseases, incurring a big medical loss. At present,active treatment to resolve the etiology (tPA, etc.) is performed forsome of the patients suffering from cerebro-embolism andcerebro-thrombus, but it can be applied only to several percentages ofthe patients due to limited time-window for treatment. In most cases,only maintenance therapy of inhibiting cerebral edema and suppressingrecurrence or enlargement (thrombolytics) has been performed, buteffective drugs for treating the etiology or protecting the brain havenot been developed. So far, many drugs having various mechanisms (e.g.,glutamate antagonist, calcium antagonist, antioxidant, etc.) have beentried, but most of them have failed in the clinical trials.

Clinical efficacy of the brain-hypothermia therapy as a brain protectingtherapy, has been studied, with building up intensive care system forcerebral stroke. Brain-hypothermia therapy is a therapy that maintainsthe brain temperature (cerebral temperature) low as 32 to 33° C., whichhas prominent brain-protecting effects. Therefore, this therapy has beendrawing attention. However, this therapy requires 24-hour intensive careby intensive treatment facility and many staffs, which makes itdifficult to be accepted as a general therapy.

On the other hand, the following compounds have been reported as acompound which has an aminoacyl group on the benzene ring of a bicyclicheterocycle in which the benzene is fused with a 5-membered heterocycle.

1) A compound represented by the following Formula

[wherein, R³ is an acylamino group, etc.] (Pamphlet of WO02/085866)which has analgesic action.

2) A compound represented by the following Formula

[wherein, W is an acylamino group, etc.] which has proliferating anddifferentiating action on stem cells or precursor cells of neuron(JP-A-2002-348239).

3) A compound represented by the following Formula

[wherein, the group NR¹R² is an amincacyl group, etc.] which has sodiumchannel regulating action (Pamphlet of WO98/08842).

DISCLOSURE OF INVENTION

Cerebrovascular disorders are broadly classified into cerebralinfarction, cerebral hemorrhage and subarachnoid hemorrhage. For thetreatment, a confirmation waiting time for a proper diagnosis by X-ray,CT or MRI image diagnosis is required, which limits time-window fortreatment.

However, a cannabinoid receptor agonist can resolve the problem oftime-window for treatment since it is not selective for a certain typeof disease. Further, a cannabinoid receptor agonist is expected to be auseful agent of preventing, treating or diagnosing cerebrovasculardisorders such as cerebral infarction, cerebral hemorrhage, subarachnoidhemorrhage, etc., or head injury, or various inflammatory diseases. Inaddition, it eliminates the need for heavy intensive care system by theintensive treatment facilities and staffs which are normally required inthe hypothermia therapy, but is expected to exert equivalent brainprotecting effects to the hypothermia therapy.

Therefore, the object of the present invention is to provide a benzenering-fused 5-membered heterocyclic compound, having excellent modulatingaction on cannabinoid receptor function.

The present inventors have made extensive studies to solve aboveproblems, and as results, have found unexpectedly that the compoundsrepresented by Formula (I₀), (I), (I′) and (I″) which have an aminoacylgroup on the benzene-fused 5-membered heterocyclic group, have excellentmodulating action on cannabinoid receptor function, to complete thepresent invention.

That is, the present invention provides the followings:

(1) a cannabinoid receptor modulator containing a compound representedby Formula (I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R⁰ is an optionally substitutedacylamino group, ring A₀ is a benzene ring which may further have asubstituent in addition to R⁰, and ring B is an optionally substituted5-membered heterocycle, or a salt thereof or a prodrug thereof,

(2) the modulator as described in (1) wherein the compound representedby Formula)(I₀) or a salt thereof or a prodrug thereof is a compoundrepresented by Formula (I)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R¹, R², R³ and R⁴ areindependently a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an optionallysubstituted hydroxyl group, an optionally substituted mercapto group oran optionally substituted amino group, or R² and R³ may be takentogether to form a bond, or R¹ and R² may be taken with the adjacentcarbon atom to form an optionally substituted ring, Y is —CO—, —SO—, or—SO₂—, R⁵ is a hydrogen atom or an optionally substituted hydrocarbongroup, R⁶ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group or an optionallysubstituted amino group, or R⁵ and R⁶ may be taken with the adjacentcarbon atom or sulfur atom and nitrogen atom to form an optionallysubstituted ring, and ring A is a benzene ring which may further have asubstituent in addition to a group represented by the following formula

wherein, each symbol has the same meaning as described above, or a saltthereof or a prodrug thereof,

(3) the modulator as described in (2) wherein R¹ and R² are a hydrogenatom,

(4) the modulator as described in (2) wherein R¹ and R² are respectivelya hydrogen atom or a C₁₋₄ alkyl group, provided that R¹ and R² are not ahydrogen atom at the same time,

(5) the modulator as described in (1) wherein the compound representedby Formula (I₀) or the salt thereof is a cannabinoid receptor agonist,

(6) the modulator as described in (5) wherein cannabinoid receptor istype 1 cannabinoid receptor,

(7) the modulator as described in (1) wherein the compound representedby Formula (I₀) or the salt thereof is a cannabinoid receptorantagonist,

(8) the modulator as described in (7) wherein the cannabinoid receptoris type 1 cannabinoid receptor,

(9) the modulator as described in (1) wherein the compound representedby Formula (I₀) or a salt thereof is type 2 cannabinoid receptoragonist,

(10) the modulator as described in (1) which is an agent of preventing,treating or pain-relieving acute cerebrovascular disorders, spinaldamage, head injury, multiple sclerosis, glaucoma, depression, vomit,arthritis or asthma,

(11) the modulator as described in (1) which is an agent of preventingor treating memory disorders, psychiatric diseases, obesity, mentaldiseases, anxiety, depression, drug-dependency, Alzheimer's dementia orParkinson's disease, or an aid for smoking cessation,

(12) the modulator as described in (1) which is an agent of preventingor treating multiple sclerosis, neurodegenerative diseases, irritablebowel syndrome, Crohn's Disease, reflux oesophagitis, COPD, psoriasis,autoimmune diseases, graft rejection, allergic diseases, neuropathicpain, hepatitis virus or hypertension, or an agent of regulatingimmunity,

(13) a compound represented by Formula (I′)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R¹ and R² are independently ahydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted heterocyclic group, an optionally substitutedhydroxyl group, an optionally substituted mercapto group or anoptionally substituted amino group, or R¹ and R² may be taken with theadjacent carbon atom to form an optionally substituted ring, R³ is ahydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group, an optionally substitutedmercapto group or an optionally substituted amino group, R⁴′ is ahydrogen atom, an optionally substituted alkyl group, an optionallysubstituted aryl group, or an optionally substituted heterocyclic group,Y is —CO—, —SO—, or —SO₂—, R⁵ is a hydrogen atom or an optionallysubstituted hydrocarbon group, R⁶′ is an optionally substitutedhydrocarbon group (provided that both of R¹ and R² are not a hydrogenatom, R⁶′ has no benzene ring), an optionally substituted hydroxyl groupor an optionally substituted amino group, and ring A′ is a benzene ringwhich may have further substituent in addition to a group represented bythe following formula

wherein, each symbol has the same meaning as described above,or a salt thereof,

(14) the compound as described in (13) wherein R¹ and R² areindependently a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an optionallysubstituted hydroxyl group, an optionally substituted mercapto group oran optionally substituted amino group,

(15) the compound as described in (13) wherein R¹ and R² are a hydrogenatom,

(16) the compound as described in (13) wherein R¹ and R² arerespectively a hydrogen atom or a C₁₋₄ alkyl group, provided that R¹ andR² are not a hydrogen atom at the same time,

(17) the compound as described in (13) wherein R³′ is a hydrogen atom,

(18) the compound as described in (13) wherein R⁴′ is an optionallysubstituted C₆₋₁₄ aryl group or an optionally substituted 5 to14-membered heterocyclic group,

(19) the compound as described in (13) wherein R⁴ is an optionallysubstituted phenyl group,

(20) the compound as described in (19) wherein R⁴ is a phenyl groupwhich may be substituted with an optionally substituted C₁₋₄ alkyl groupor an optionally substituted C₁₋₄ alkoxy group,

(21) the compound as described in (13) wherein Y is —CO—,

(22) the compound as described in (13) wherein R⁵ is a hydrogen atom,

(23) the compound as described in (13) wherein X is an oxygen atom,

(24) the compound as described in (13) wherein 5-position of thefused-heterocycle in Formula (I′) is substituted by a group representedby the following formula

wherein, each symbol has the same meaning as described above,

(25) the compound as described in (24) wherein 7-position of thefused-heterocycle in Formula (I′) is further substituted by anoptionally substituted C₆₋₁₄ aryl-C₁₋₄ alkyl group,

(26) the compound as described in (25) wherein the optionallysubstituted C₆₋₁₄ aryl-C₁₋₄ alkyl group is an optionally substitutedbenzyl group,

(27) the compound as described in (13) wherein ring A′ is a benzene ringwhich may further have 1 to 3 substituents selected from an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₆₋₁₂ arylgroup, an optionally substituted 5- or 6-membered heterocyclic group andan acyl group in addition to a group represented by the followingformula

wherein, each symbol has the same meaning as described above,

(28) the compound as described in (27) wherein 7-position of thefused-heterocycle in Formula (I₀) is substituted by an optionallysubstituted C₁₋₄ alkyl group, an optionally substituted C₆₋₁₂ arylgroup, an optionally substituted 5- or 6-membered heterocyclic group, oran acyl group,

(29) the compound as described in (27) wherein 7-position of thefused-heterocycle in Formula (I₀) is substituted by an phenyl group, afuranyl group, a thienyl group, a pyridyl group, an acetyl group, apropionyl group, a butyryl group, or a benzoyl group, which may besubstituted, respectively,

(30)N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,

-   (+)-N-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   N-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   (+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   (+)-N-(tert-butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea,-   N-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   N-(7-(3-dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   N-(3-hydroxypropyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea,-   N-((4-isopropyl-3-(2-methoxyethoxy)-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   N-(7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,-   N-(3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide,    or-   N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1′-cyclopentan)-5-yl)-3,3-dimethylbutanamide,

(31) a prodrug of the compound as described in (13),

(32) a drug comprising the compound as described in (13) or a prodrugthereof,

(33) a method of preventing treating or pain-relieving acutecerebrovascular disorders, spinal damage, head injury, multiplesclerosis, glaucoma, depression, vomit, arthritis or asthma, which ischaracterized by administering an effective amount of a compoundrepresented by Formula (I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R⁰ is an acylamino group, ring A₀is a benzene ring which may further have a substituent in addition toR⁰, and ring B is an optionally substituted 5-membered heterocycle, or asalt thereof or a prodrug thereof to a subject in need of suchtreatment,

(34) a method of preventing or treating memory disorders, psychiatricdiseases, obesity, mental diseases, anxiety, depression,drug-dependency, Alzheimer's dementia or Parkinson's disease, or amethod of aiding smoking cessation, which is characterized byadministering an effective amount of a compound represented by Formula(I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino-group, R⁰ is an acylamino group, ring A₀is a benzene ring which may further have a substituent in addition toR⁰, and ring B is an optionally substituted 5-membered heterocycle, or asalt thereof or a prodrug thereof to a subject in need of suchtreatment,

(35) a method of preventing or treating multiple sclerosis,neurodegenerative diseases, irritable bowel syndrome, Crohn's Disease,reflux oesophagitis, COPD, psoriasis, autoimmune diseases, graftrejection, allergic diseases, psychogenic pain, hepatitis virus orhypertension, or a method of regulating immunity, which is characterizedby administering an effective amount of a compound represented byFormula (I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R⁰ is an acylamino group, ring A₀is a benzene ring which may further have a substituent in addition toR⁰, and ring B is an optionally substituted 5-membered heterocycle, or asalt thereof or a prodrug thereof to a subject in need of suchtreatment,

(36) use of a compound represented by Formula (I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R⁰ is an acylamino group, ring A₀is a benzene ring which may further have a substituent in addition toR⁰, and ring B is an optionally substituted 5-membered heterocycle, or asalt thereof or a prodrug thereof, for manufacturing an agent ofpreventing or treating acute cerebrovascular disorders, spinal damage,head injury, multiple sclerosis, glaucoma, depression, vomit, arthritisor asthma; or for manufacturing an analgesic agent,

(37) use of a compound represented by Formula (I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R⁰ is an acylamino group, ring ADis a benzene ring which may further have a substituent in addition toR⁰, and ring B is an optionally substituted 5-membered heterocycle, or asalt thereof or a prodrug thereof, for manufacturing an agent ofpreventing or treating memory disorders, psychiatric diseases, obesity,mental diseases, anxiety, depression, drug-dependency, Alzheimer'sdementia or Parkinson's disease, or an aid for smoking cessation,

(38) use of a compound represented by Formula (I₀)

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group, R⁰ is an acylamino group, ring A₀is a benzene ring which may further have a substituent in addition toR⁰, and ring B is an optionally substituted 5-membered heterocycle, or asalt thereof or a prodrug thereof, for manufacturing an agent ofpreventing or treating multiple sclerosis, neurodegenerative diseases,irritable bowel syndrome, Crohn's Disease, reflux oesophagitis, COPD,psoriasis, autoimmune diseases, graft rejection, allergic diseases,neuropathic pain, hepatitis virus or hypertension, or an agent ofregulating immunity, and

(39) a method of preparing a compound represented by the followingformula

wherein, each symbol has the same meaning as described below, or a saltthereof, comprising reacting a compound represented by the followingformula

wherein, X is an oxygen atom, an optionally substituted sulfur atom oran optionally substituted imino group,

R¹, R², R³ and R⁴ are independently a hydrogen atom, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an optionally substituted hydroxyl group, an optionallysubstituted mercapto group or an optionally substituted amino group, orR² and R³ may be taken together to form a bond, or R¹ and R² may betaken with the adjacent carbon atom to form an optionally substitutedring,

R⁵ is a hydrogen atom or an optionally substituted hydrocarbon group, R⁶is a hydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted hydroxyl group or an optionally substituted aminogroup, or R⁵ and R⁶ may be taken with the adjacent carbon atom or sulfuratom and nitrogen atom to form an optionally substituted ring, and

ring A is a benzene ring which may have further substituent in additionto a group represented by Formula —NHR⁵ (wherein, each symbol has thesame meaning as described above), or a salt thereof with,

R⁶YL, (R⁶Y)₂O or R⁶N═Y, wherein, L is a leaving group, and Y is —CO—,—SO—, or —SO₂—.

In addition, as alternative embodiments, the present invention providesthe followings:

(1′) a cannabinoid receptor modulator containing the compoundrepresented by Formula (I₀) or a salt thereof or a prodrug thereof,

(2′) the modulator as described in (1′) wherein the compound representedby Formula (I₀) or a salt thereof or a prodrug thereof is a compoundrepresented by Formula (I) or a salt thereof or a prodrug thereof,

(3′) the modulator as described in (2′) wherein R¹ and R² arerespectively a hydrogen atom,

(4′) the modulator as described in (2′) wherein R¹ and R² arerespectively a C₁₋₄ alkyl group,

(5′) the modulator as described in (2′) wherein R³ is a hydrogen atom,

(6′) the modulator as described in (2′) wherein R⁴ is an optionallysubstituted C₆₋₁₄ aryl group or an optionally substituted 5 to14-membered heterocycle,

(7′) the modulator as described in (2′) wherein R⁵ is a hydrogen atom,

(8′) the modulator as described in (2′) wherein R⁶ is an optionallysubstituted alkyl group or an optionally substituted amino group, and Yis —CO—,

(9′) the modulator as described in (2′) wherein R¹, R², R³ and R⁴ areindependently a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an optionallysubstituted hydroxyl group, an optionally substituted mercapto group oran optionally substituted amino group,

(10′) the modulator as described in (1′) wherein X is an oxygen atom,

(11′) the modulator as described in (1′) wherein R⁰ is substituted at5-position of the fused-heterocycle in Formula (I₀),

(12′) the modulator as described in (11′) wherein the optionallysubstituted C₆₋₁₄ aryl-C₁₋₄ alkyl group is further substituted at7-position of the fused-heterocycle in Formula (I₀),

(13′) the modulator as described in (1′) wherein ring A₀ is a benzenering further having 1 to 3 C₁₋₆ alkyl groups in addition to R⁰,

(14′) the modulator as described in (1′) wherein the compoundrepresented by Formula (I₀) or a salt thereof is a cannabinoid receptoragonist,

(15′) the modulator as described in (14′) wherein the cannabinoidreceptor is type 1 cannabinoid receptor,

(16′) the modulator as described in (1′) wherein the compoundrepresented by Formula (I₀) or a salt thereof is a cannabinoid receptorantagonist,

(17′) the modulator as described in (16′) wherein the cannabinoidreceptor is type 1 cannabinoid receptor,

(18′) the modulator as described in (1′) which is an agent of preventingor treating acute cerebrovascular disorders, spinal damage, head injury,multiple sclerosis, glaucoma, or asthma,

(19′) the modulator as described in (1′) which is an agent of preventingor treating memory disorders, psychiatric diseases, or obesity,

(20′) a compound represented by Formula (I″)

wherein, R³′ is a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted hydroxyl group, an optionallysubstituted mercapto group or an optionally substituted amino group, R⁴′is an optionally substituted aryl group, or an optionally substitutedheterocyclic group, ring A′ is a benzene ring which may have furthersubstituent in addition to a group represented by the following formula

wherein, each symbol has the same meaning as described above, and othersymbols have same meanings as defined in (2′),or a salt thereof,

(21′) the compound as described in (20′) wherein R³′ is a hydrogen atom,

(22′) the compound as described in (20′) wherein R⁴′ is an optionallysubstituted C₆₋₁₄ aryl group or an optionally substituted 5 to14-membered heterocyclic group,

(23′) the compound as described in (20′) wherein R⁴′ is an optionallysubstituted phenyl group,

(24′) the compound as described in (20′) wherein X is an oxygen atom,

(25′) the compound as described in (20′) wherein 5-position of thefused-heterocycle in Formula (I″) is substituted by a group representedby the following formula

wherein, each symbol has the same meaning as described above,

(26′) the compound as described in (20′) wherein ring A is a benzenering further having 1 to 3 C₁₋₆ alkyl groups in addition to a grouprepresented by the following formula

wherein, each symbol has the same meaning as described above,

(27′) a prodrug of the compound as described in (20′),

(28′) a drug comprising the compound as described in (20′) or theprodrug as described in (27′),

(29′) a pharmaceutical composition comprising the compound as describedin (20′) or the prodrug as described in (27′) and a pharmaceuticallyacceptable carrier.

According to the present invention, an excellent cannabinoid receptormodulator is provided. In addition, a novel compound represented by theabove-mentioned Formula (I′) and (I″) or a salt thereof is provided.

DETAILED DESCRIPTION OF THE INVENTION

The compound represented by Formula (I₀) or a salt thereof [hereinafter,it may be abbreviated as Compound (I₀).] is preferably the compoundrepresented by Formula (I) [hereinafter, it may be abbreviated asCompound (I).] or a salt thereof. As mentioned above, the compoundsrepresented by Formula (I′) and (I″) or a salt thereof which arecontained in Compound (I₀) and Compound (I), are novel compounds[hereinafter, the compound represented by Formula (I′) will beexplained, but explanations for the compound represented by Formula (I′)are also applied to the compound represented by Formula (I″). Further,the compound represented by Formula (I′) or a salt thereof may beabbreviated as Compound (I′).].

The acylamino group represented by R⁰ in the above-mentioned formulasis, for example, an acylamino group represented by the following formula

wherein, Y is —CO—, —SO—, or —SO₂—, R⁵ is a hydrogen atom or anoptionally substituted hydrocarbon group, R⁶ is a hydrogen atom, anoptionally substituted hydrocarbon group, an optionally substitutedhydroxyl group or an optionally substituted amino group, or R⁵ and R⁶may be taken with an adjacent carbon atom or a sulfur atom and anitrogen atom to form an optionally substituted ring, etc.

As used herein, Y is preferably —CO—, R⁵ is preferably a hydrogen atom,etc., and R⁶ is preferably an optionally substituted hydrocarbon groupor an optionally substituted amino group, etc.

The hydrocarbon group of the “optionally substituted hydrocarbon group”represented by R⁵, R⁶ and R⁶′ is, for example, a chain or cyclichydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkandienyl, aryl, etc.) or a combined group thereof(e.g., C₇₋₁₄ aralkyl such as benzyl; C₂₋₆alkyl-C₆₋₁₄ aryl such asethylphenyl, propylphenyl, etc.; C₂₋₆alkenyl-C₆₋₁₄ aryl such asvinylphenyl, isopropenylphenyl, etc.), or the like. Among these, a Cl₁₆chain or cyclic hydrocarbon group, etc. are preferred. Among these,alkyl is preferred for R⁶.

The “alkyl” is preferably, for example, C₁₋₁₀ alkyl (e.g., methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl,1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl, etc.), or the like. Amongthese, C₁₋₆ alkyl is further preferred, and C₁₋₄ alkyl is especiallypreferred for R⁵. On the other hand, C₂₋₁₀ alkyl is further preferred,and C₂₋₆alkyl is especially preferred for R⁶.

The “alkenyl” is preferably, for example, C₂₋₆ alkenyl (e.g., vinyl,allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, etc.), or the like.

The “alkynyl” is preferably, for example, C₂₋₆ alkynyl (e.g., ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, etc.), or the like.

The “cycloalkyl” is preferably, for example, C₃₋₆ cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), or the like.

The “cycloalkenyl” is preferably, for example, C₃₋₆ cycloalkenyl (e.g.,2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc.), or thelike.

The “cycloalkandienyl” is preferably, for example, C₅₋₆ cycloalkandienyl(e.g., 2,4-cyclopentandien-1-yl, 2,4-cyclohexandien-1-yl,2,5-cyclohexandien-1-yl, etc.), or the like.

The “aryl” is preferably, for example, C₆₋₁₄ aryl (e.g., phenyl,1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.), or the like.

The “aralkyl” is preferably, for example, C₆₋₁₄ aryl-C₁₋₆ alkyl group(e.g., benzyl, α-methylbenzyl, etc.), or the like.

The “substituent” of the “optionally substituted hydrocarbon group” ispreferably, for example, (1) a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.), (2) C₁₋₃ alkylenedioxy (e.g., methylenedioxy,ethylenedioxy, etc.), (3) nitro, (4) cyano, (5) an optionallyhalogenated or hydroxylated C₁₋₆ alkyl, (6) an optionally halogenatedC₂₋₆ alkenyl, (7) an optionally halogenated C₂₋₆ alkynyl, (8) anoptionally halogenated C₃₋₆ cycloalkyl, (9) C₆₋₁₄ aryl (e.g., phenyl,1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.), (10) an optionallyhalogenated or acylated C₁₋₆ alkoxy, (11) an optionally halogenated C₁₋₆alkylthio or mercapto, (12) hydroxy, (13) amino, (14) mono-C₁₋₆alkylamino (e.g., methylamino, ethylamino, etc.), (15) mono-C₆₋₁₄arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.),(16) di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino, etc.), (17)di-C₆₋₁₄ arylamino (e.g., diphenylamino, etc.), (18) acyl, (19)acylamino, (20) acyloxy, (21) an optionally substituted 5- to 7-memberedsaturated cyclic amino, (22) a 5- to 10-membered heterocyclic group(e.g., 5- to 10-membered aromatic heterocyclic group such as 2- or3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4-or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, benzo[b]furanyl, etc.; a 5- to 10-memberednon-aromatic heterocyclic group such as 1,3-dioxolan-2-yl, etc.), (23)sulfo, (24) C₆₋₁₄ aryloxy (e.g., phenyloxy, naphthyloxy, etc.) or (25)oxo, etc.

The “hydrocarbon group” may have, for example, the 1 to 5, preferably 1to 3 above-mentioned substituents at any substitutable position, and ifthe number of substituent is two or more, each substituent is the sameor different.

The above-mentioned “optionally halogenated or hydroxylated C₁₋₆ alkyl”is, for example, C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which maybe substituted with 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine, etc.) or hydroxyl group, etc.Specific examples are methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl,isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,6,6,6-trifluorohexyl, etc.

The above-mentioned “optionally halogenated C₂₋₆ alkenyl” is, forexample, C₂₋₆ alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl,isobutenyl, sec-butenyl, etc.) which may be substituted with 1 to 5,preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine,iodine, etc.), or the like. Specific examples are vinyl, allyl,isopropenyl, butenyl, isobutenyl, sec-butenyl,3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl, etc.

The above-mentioned “optionally halogenated C₂₋₆ alkynyl” is, forexample, C₂₋₆ alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl,etc.) which may be substituted with 1 to 5, preferably 1 to 3 halogenatoms (e.g., fluorine, chlorine, bromine, iodine, etc.), or the like.Specific examples are ethynyl, propargyl, butynyl, 1-hexynyl,3,3,3-trifluoro-1-propynyl, 4,4,4-trifluoro-1-butynyl, etc.

The above-mentioned “optionally halogenated C₃₋₆ cycloalkyl” is, forexample, C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.) which may be substituted with 1 to 5, preferably 1 to3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), orthe like. Specific examples are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl, etc.

The above-mentioned “optionally halogenated, hydroxylated, alkoxylatedor acylated C₁₋₆ alkoxy” is, for example, C₁₋₆ alkoxy (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy,hexyloxy, etc.) which may be substituted with 1 to 5, preferably 1 to 3substituents selected from a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.), a hydroxyl group, a C₁₋₆ alkoxy group (e.g.,methoxy, ethoxy, etc.), or an acyl group (e.g., C₁₋₆ alkyl-carbonyl suchas acetyl and propionyl; C₁₋₆ alkoxy-carbonyl such as methoxycarbonyland ethoxycarbonyl), etc. Specific examples are methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, etc.

The above-mentioned “optionally halogenated C₁₋₆ alkylthio.” is, forexample, C₁₋₆ alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which maybe substituted with 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine, etc.), or the like. Specificexamples are methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio,4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.

The above-mentioned “acyl” is, for example, formyl, carboxyl, carbamoyl,C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C₃₋₆cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, etc.), C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C₆₋₁₄aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C₇₋₁₆aralkyl-carbonyl (e.g., phenylacetyl, phenylpropionyl, etc.), C₆₋₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C₇₋₁₆aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl,etc.), 5- or 6-membered heterocyclic carbonyl (e.g., nicotinoyl,isonicotinoyl, 2-tenoyl, 3-tenoyl, 2-furoyl, 3-furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl,1-pyrrolidinylcarbonyl, etc.), mono-C₁₋₆ alkyl-carbamoyl (e.g.,methylcarbamoyl, ethylcarbamoyl, etc.), di-C₁₋₆ alkyl-carbamoyl (e.g.,dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C₆₋₁₄aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl, etc.), thiocarbamoyl, 5- or 6-membered heterocycliccarbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C₁₋₆alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C₆₋₁₄arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl, etc.), C₁₋₆ alkylsulfinyl (e.g., methylsulfinyl,ethylsulfinyl, etc.), C₆₋₁₄ arylsulfinyl (e.g., phenylsulfinyl,1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), or the like.

The above-mentioned “acylamino” is, for example, formylamino, C₁₋₆alkyl-carbonylamino (e.g., acetylamino, etc.), C₆₋₁₄ aryl-carbonylamino(e.g., phenylcarbonylamino, naphthylcarbonylamino, etc.), C₁₋₆alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino,propoxycarbonylamino, butoxycarbonylamino, etc.), C₁₋₆alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino,etc.), C₆₋₁₄ arylsulfonylamino (e.g., phenylsulfonylamino,2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), or the like.

The above-mentioned “acyloxy” is, for example, C₁₋₆ alkyl-carbonyloxy(e.g., acetoxy, propionyloxy, etc.), C₆₋₁₄ aryl-carbonyloxy (e.g.,benzoyloxy, naphthylcarbonyloxy, etc.), C₁₋₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy, etc.), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C₁₋₆ alkyl-carbamoyloxy(e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C₆₋₁₄aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy,etc.), nicotinoyloxy, etc.

The above-mentioned “optionally substituted 5- to 7-membered saturatedcyclic amino” of the “5- to 7-membered saturated cyclic amino” is, forexample, morpholino, thiomorpholino, piperazin-1-yl, piperidino,pyrrolidin-1-yl, etc. The “substituent” of the “optionally substituted5- to 7-membered saturated cyclic amino” is, for example, C₁₋₆ alkyl(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, etc.), C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl,2-naphthyl, biphenylyl, 2-anthryl, etc.), 5- to 10-membered aromaticheterocyclic group (e.g., 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-,4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.), or thelike. The “5- to 7-membered saturated cyclic amino” may have 1 to 3substituents.

The substituent in the “optionally substituted hydroxyl group” and the“optionally substituted amino group” represented by R⁶ and R⁶′ are, forexample, one as defined in the “optionally substituted hydrocarbongroup” represented by R⁵ and R⁶ and the substituent thereof. The “aminogroup” may have 1 to 2 substituents.

The “ring” that R⁵ and R⁶ may be taken with the adjacent carbon atom andthe nitrogen atom to form is, for example, a 5- to 7-membered saturatedor non-saturated nitrogen-containing heterocycle which may contain 1 to2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogenatom, etc. as a ring-constituting atom in addition to nitrogen atom(e.g., pyrrolidin-2-one, thiazolidin-2-one, thiazolidin-4-one,oxazolidin-2-one, oxazolidin-4-one, imidazolidin-2-one,imidazolidin-4-one, piperidin-2-one, thiazinan-4-one,thiomorpholin-3-one, azepan-2-one, dihydropyrrol-2-one,dihydropyridine-2-one, pyridine-2-one, tetrahydroazepin-2-one,dihydroazepin-2-one, etc.), or the like. The heteroatom in the“nitrogen-containing heterocycle” is preferably 1 to 2 kinds. This“ring” may have further substituent in addition to oxo group. The“substituent” is, for example, one as defined in the substituent of the“optionally substituted hydrocarbon group” represented by R⁵ and R⁶. Thenumber of the “substituent” is, for example, 1 to 5 (preferably 1 to 3,further preferably is 1 to 2).

The substituent that ring A₀ in the above-mentioned formulas may furtherhave in addition to R⁰, the substituent that ring A in theabove-mentioned formulas may further have in addition to a grouprepresented by the following formula

wherein, each symbol has the same meaning as described above, and thesubstituent that ring A′ in the above-mentioned formulas may furtherhave in addition to a group represented by the following formula

wherein, each symbol has the same meaning as described above(hereinafter, these may be referred to simply as the substituent thatring A, etc. may further have) are, for example, an optionallysubstituted hydrocarbon group, an optionally substituted heterocyclicgroup, an acyl group, an optionally substituted hydroxyl group, anoptionally substituted amino group, a halogen atom (e.g., fluorine,chlorine, bromine, iodine), or dihydroxyboryl, etc. The “optionallysubstituted hydrocarbon group”, the “optionally substituted hydroxylgroup” and the “optionally substituted amino group” are, for example,one as defined in the “optionally substituted hydrocarbon group”, the“optionally substituted hydroxyl group” and the “optionally substitutedamino group”, respectively represented by R⁶. The “optionallysubstituted heterocyclic group” is, for example, one as defined in the“optionally substituted heterocyclic group” as the “substituent ofoptionally substituted 5-membered heterocycle represented by ring B” inthe below. The “acyl group” is exemplified by those for the acyl groupin the acylamino represented by R⁰:R⁶—Y—.

Among these, the substituent that ring A, etc. may further have, ispreferably an optionally substituted C₁₋₆ alkyl group, an optionallysubstituted C₆₋₁₂ aryl group, an optionally substituted 5- or 6-memberedheterocyclic group, or an acyl group. Especially, when 7-position (inthe following formula, represented by number 7.) of thefused-heterocycle in Formula (I₀), Formula (I) and Formula (I′) issubstituted by the substituent that ring A, etc. may further have, anoptionally substituted C₆₋₁₄ aryl-C₁₋₆ alkyl group is also preferred.The “C₆₋₁₄ aryl-C₁₋₆ alkyl group” of the “optionally substituted C₆₋₁₄aryl-C₁₋₆ alkyl group” is, for example, benzyl, α-methylbenzyl, etc.,and the substituent thereof is, for example, one as defined in thesubstituent of the “optionally substituted hydrocarbon group”represented by R⁶.

The number of the “substituent” that ring A, etc. may further have is,for example, 1 to 3 (preferably 2 to 3). When the number of the“substituent” that ring A, etc. may further have is 2 or more, 2substituents among them may form an optionally substituted 5 to6-membered ring with the carbon atom to which they are bonded. The “5 to6-membered ring” is preferably a saturated or non-saturated C₅₋₆carbonic ring. The substituent of the “5 to 6-membered ring” is, forexample, a C₁₋₆ alkyl group, a C₁₋₆alkoxy group, a nitro group, ahydroxyl group, an amino group or a halogen atom, etc.

The “optionally substituted 5-membered heterocycle” represented by ringB in the above-mentioned formulas is preferably a ring represented bythe following formula

wherein, each symbol is as defined in Formula (I). As used herein, whenR² and R³ are taken together to represent a bond, this ring is,

5-membered ring represented by the following formula

wherein, each symbol is as defined in Formula (I).

The “optionally substituted sulfur atom” represented by X in theabove-mentioned formulas is preferably a non-substituted sulfur atom oran oxidized sulfur atom (e.g., SO, SO₂). Further, the substituent of the“optionally substituted imino group” represented by X in theabove-mentioned formulas is, for example, a C₁₋₆ alkyl group or a C₂₋₆alkenyl group which may be substituted with a halogen atom, a cyanogroup, a nitro group or a hydroxyl group, respectively.

In other words, a 5-membered heterocycle of the “optionally substituted5-membered heterocycle” represented by ring B is, for example,dihydropyrrole, ethene, pyrrole, dihydrothiophene,dihydrothiophene-1-oxide, dihydrothiophene-1,1-dioxide, thiophene,dihydrofuran or furan.

The substituent of the “optionally substituted 5-membered heterocycle”in the above-mentioned formulas represented by ring B is, for example,an optionally substituted hydrocarbon group, an optionally substitutedhydroxyl group, an optionally substituted amino group, an optionallysubstituted heterocyclic group, or an optionally substituted mercaptogroup, etc. Ring B may have 1 to 5 (preferably 2 to 4) substituents.When ring B is non-substituted, ring A, ring A₀, and ring A′ arepreferably substituted with the above-mentioned “optionally substitutedC₆₋₁₄ aryl-C₁₋₆ alkyl group” at 7-position of the fused-heterocycle inFormula (I₀), Formula (I) and Formula (I′), respectively.

The “optionally substituted hydrocarbon group”, the “optionallysubstituted hydroxyl group”, and the “optionally substituted aminogroup” are, for example, ones as defined in the “optionally substitutedhydrocarbon group”, the “optionally substituted hydroxyl group”, and the“optionally substituted amino group” represented by R⁶, respectively.

The “heterocyclic group” of the “optionally substituted heterocyclicgroup” is preferably a 5- to 14-membered heterocyclic group. The 5- to14-membered heterocyclic group is, for example, a 5- to 14-memberedheterocyclic group (aromatic heterocyclic group, saturated ornon-saturated non-aromatic heterocyclic group) containing at least 1(preferably 1 to 4) of one to three kinds of heteroatoms selected fromnitrogen atom, sulfur atom and oxygen atom in addition to carbon atom,etc.

The “aromatic heterocyclic group” is, for example, a 5- to 14-membered(preferably 5- to 10-membered) aromatic heterocyclic group containing atleast 1 heteroatoms selected from a nitrogen atom, a sulfur atom and anoxygen atom (for example, 1 to 4) in addition to a carbon atom, etc.Specific examples are aromatic heterocycle such as thiophene,benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole,benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolidine,xanthrene, phenoxathine, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole,purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine,naphthiridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acrydine, phenazine, thiazole, isothiazole,phenothiazine, oxazole, isoxazole, furazane, phenoxazine, etc., or agroup obtained by subtracting any one hydrogen atom from a ring which isformed by fusion of such ring (s) (preferably, single ring) with one ormore (preferably 1 or 2) aromatic ring (e.g., benzene ring, etc.), orthe like. The examples include 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, 2- or 3-thienyl,etc.

The “non-aromatic heterocyclic group” is, for example, a 3 to 8-membered(preferably 5- or 6-membered) saturated or non-saturated non-aromaticheterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl, piperazinyl, etc.

The substituent of the “optionally substituted heterocyclic group” is,for example, one as defined in the “optionally substituted hydrocarbongroup” represented by R⁵ and R⁶.

The substituent of the “optionally substituted mercapto group” is, forexample, one as defined in the substituent of the “optionallysubstituted hydrocarbon group” represented by R⁵ and R⁶.

The optional substituent of these groups may be substituted in thenumber of 1 to 5 (preferably 1 to 4, further preferably 1 to 2) at anysubstitutable position.

The “optionally substituted hydrocarbon group”, the “optionallysubstituted heterocyclic group”, the “optionally substituted hydroxylgroup”, the “optionally substituted mercapto group” and the “optionallysubstituted amino group” represented by R¹, R², R³, R³ and R⁴ in theabove-mentioned formulas are, for example, ones as defined in thesubstituent of the “optionally substituted 5-membered heterocycle”represented by ring B.

Among these, a hydrogen atom, a C₁₋₄ alkyl group (e.g., methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), or thelike, are preferred respectively for R¹, R², R³, and R³′. A hydrogenatom, etc. are further preferred for R³ and R^(3a).

In addition, among these, an optionally substituted alkyl group, anoptionally substituted aryl group, and an optionally substitutedheterocyclic group, etc. are preferred for R⁴.

The “alkyl group” of the “optionally substituted alkyl group” is, forexample, one as defined in the “alkyl group” exemplified for R⁵, R⁶ andR⁶′. The substituent of the “optionally substituted alkyl group” is, forexample, one as defined in the “substituent” of the “optionallysubstituted hydrocarbon group” which is a substituent of the “optionallysubstituted 5-membered heterocycle” represented by ring B.

The “aryl group” of the “optionally substituted aryl group” (and the“optionally substituted aryl group” represented by R⁴′) is, for example,C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl,etc.), or the like. The substituent of the “optionally substituted arylgroup” is, for example, one as defined in the “substituent” of the“optionally substituted hydrocarbon group” which is a substituent of the“optionally substituted 5-membered heterocycle” represented by ring B.

The heterocyclic group of the “optionally substituted heterocyclicgroup” (and the “optionally substituted heterocyclic group” representedby R⁴′) is, for example, one as defined in the “optionally substitutedheterocyclic group” as substituent of the “optionally substituted5-membered heterocycle” represented by ring B.

R⁴ (and R⁴′) is especially preferably an optionally substituted phenylgroup, and most preferably, a phenyl group which may be substituted withan optionally substituted C₁₋₄ alkyl group (e.g., methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) or anoptionally substituted C₁₋₄ alkoxy group (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy). The “C₁₋₄ alkylgroup” and the “C₁₋₄ alkoxy group” are preferably substituted at4-position of the phenyl group. The “substituent” of the “optionallysubstituted C₁₋₄ alkyl group” and the “optionally substituted C₁₋₄ alkylgroup” as substituent is, for example, a nitro group, a hydroxyl group,an amino group or a halogen atom, etc.

The ring of the “optionally substituted ring” that R¹ and R² may betaken with the adjacent carbon atom to form is, for example, a 3- to8-membered homo- or heterocycle.

The “3- to 8-membered homocycle” is, for example, C₃₋₈cycloalkane, etc.

The “3- to 8-membered heterocycle” is, for example, a 3- to 8-memberedheterocycle containing 1 to 4 heteroatoms selected from nitrogen atom,sulfur atom and oxygen atom in addition to carbon atom (e.g., aziridine,azetidine, morpholine, thiomorpholine, piperazine, piperidine,pyrrolidine, hexamethyleneimine, heptamethyleneimine,hexahydropyrimidine, etc.).

The “substituent” of the “optionally substituted ring” that R¹ and R²may form with the adjacent carbon atom is, for example, one as definedin the “substituent” of the “optionally substituted hydrocarbon group”represented by the above-mentioned R⁵ and R⁶, of the same number.

The 5-positions of the fused-heterocycle in Formula (I₀), Formula (I)and Formula (I′), are preferably substituted by a group represented byR₀,

wherein, each symbol has the same meaning as described above,respectively. In other words, the compounds represented by Formula (I₀),Formula (I) and Formula (I′), respectively are preferably,

wherein, numbers around the rings indicate position number,respectively.

Salts of the compounds represented by Formula (I₀), Formula (I), andFormula (I′) (hereinafter, they may be abbreviated as Compound (I),etc.) include salts with an inorganic base (e.g., alkali metals such assodium and potassium and alkaline earth metals such as calcium andmagnesium, transitional metals such as zinc, iron and copper, etc.) orwith an organic base (e.g., organic amines such as trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine and N,N′-dibenzylethylenediamine orwith basic amino acids such as arginine, lysine, ornithine, etc.), orthe like when Compound (I) has an acidic group such as a carboxyl group.

On the other hand, when Compound (I), etc. have a basic group such as anamino group, etc., such salts include salts with inorganic acids andorganic acids (e.g., hydrochloric acid, nitric acid, sulfuric acid,phosphoric acid, carbonic acid, bicarbonic acid, formic acid, aceticacid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid,tartaric acid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,etc.), acidic amino acids such as asparaginic acid, glutamic acid, etc.

The prodrug of Compound (I), etc. means a compound which is converted toCompound (I), etc. under the physiological condition by a reaction by anenzyme, an gastric acid, etc. in the living body, that is, by enzymaticoxidation, reduction, hydrolysis, etc.; by hydrolysis with gastric acid,etc. Examples of the prodrug of Compound (I), etc. include a compoundwherein the amino group of Compound (I), etc. is acylated, alkylated orphosphorylated (e.g., a compound wherein the amino group of Compound(I), etc. is eicosanylated, alanylated, pentylaminocarbonylated,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated,tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated ortert-butylated); a compound wherein the hydroxyl group of Compound (I),etc. is acylated, alkylated, phosphorylated or converted into borate(e.g., a compound wherein the hydroxyl group of Compound (I), etc. isacetylated, palmitoylated, propanoylated, pivaloylated, succinylated,fumarylated, alanylated or dimethylaminomethylcarbonylated); a compoundwherein a carboxyl group of Compound (I), etc. is esterified or amidated(e.g., a compound wherein a carboxyl group of Compound (I), etc. isethyl esterified, phenyl esterified, carboxymethyl esterified,dimethylaminomethyl esterified, pivaloyloxymethyl esterified,ethoxycarbonyloxyethyl esterified, phthalidyl esterified,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified,cyclohexyloxycarbonylethyl esterified, methylamidated, etc.); etc. Theseprodrugs can be produced by per se known methods from Compound (I), etc.

In addition, the prodrug of Compound (I), etc. may be a compound whichis converted into Compound (I), etc. under the physiological conditionsas described in “Pharmaceutical Research and Development”, Vol. 7 (DrugDesign), pp. 163-198 published in 1990 by Hirokawa Publishing Co.

Hereinafter, the methods of producing Compound (I), etc. of the presentinvention will be explained.

Compound (I), etc. of the present invention can be produced by themethods below or analogous methods thereto.

In the following Reaction Schemes, each symbol of the compounds has thesame meaning unless otherwise stated. The compounds in Reaction Schemeinclude salts thereof, and the salts are, for example, ones as definedin Compound (I), etc.

Compound (I) can be produced by a method described in the followingReaction Scheme 1.

In Reaction Scheme 1, L is a leaving group, R⁷ is a substituent thatring A may further have in addition to a group represented by thefollowing formula

wherein, each symbol has the same meaning as described above, or acorresponding group thereto, R⁸ is a group formed by subtracting a NHgroup from an optionally substituted amino group represented by R⁶, andother symbols have the same meanings as defined above.

Compound (I) can be produced by reacting Compound (II) with Compound(IIIa), Compound (IIIb) or Compound (IV), if desired, under the presenceof base or acid.

Compound (IIIa), Compound (IIIb) or Compound (IV) is commerciallyavailable, and further can be produced by per se known methods oranalogous methods thereto.

The “leaving group” represented by L is, for example, hydroxy, a halogenatom (for example, fluorine, chlorine, bromine, iodine, etc.),optionally halogenated C₁₋₅ alkylsulfonyloxy (e.g., methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀ arylsulfonyloxy, optionally substituted phenyloxygroup, optionally substituted 2-thiobenzothiazole, etc. The “optionallysubstituted C₆₋₁₀ arylsulfonyloxy” is, for example, C₆₋₁₀arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, etc.)which may have 1 to 3 substituents selected from C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, etc.), C₁₋₆ alkoxy (e.g., methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy,etc.) or nitro, etc., specifically, benzenesulfonyloxy,m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, etc.

Compound (IIIa), Compound (IIIb) or Compound (IV) is used in an amountof about 1.0 to 10 moles, preferably about 1.0 to 2.0 moles, relative to1 mole of Compound (II).

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc., alkali metal hydridessuch as sodium hydride, potassium hydride, etc., metal amides such assodium amide, lithium diisopropylamide, lithium hexamethyldisilazide,etc., metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide, etc., or the like.

The “acid” is, for example, methanesulfonic acid, p-toluenesulfonicacid, camphor-sulfonic acid, etc.

The “base” is used in an amount of about 0.1 to 10 equivalents,preferably 0.8 to 2 equivalents, relative to Compound (II).

The “acid” is used in an amount of about 0.1 to 10 equivalents,preferably 0.8 to 3 equivalents, relative to Compound (II).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, water,ethers such as diethyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., nitriles such as acetonitrile, propionitrile, etc., sulfoxidessuch as dimethylsulfoxide, etc., nitrogen-containing aromatichydrocarbons such as pyridine, lutidine, quinoline, etc. or mixedsolvent thereof. The reaction temperature is about −40 to 150° C.,preferably 0 to 100° C. The reaction time is usually 5 minutes to 24hours, preferably 10 minutes to 5 hours.

Thus obtained product (I) may be isolated from the reaction mixture by aconventional method, and easily purified by conventional means ofseparation such as recrystallization, distillation, chromatography, etc.

Alternatively, Compound (II) and Compound (IIIa) may be reacted underthe presence of a suitable condensing agent reaction.

Compound (IIIa) is used in an amount of about 0.8 to about 10.0 moles,preferably about 0.8 to about 2.0 moles, relative to 1 mole of Compound(II).

The “condensing agent” is, for example, N,N′-dicarbodiimides such asN,N′-dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, etc.,azolides such as N,N′-carbonylimidazole, etc., a dehydrating agent suchas N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diethylcyanophosphate, phosphorus oxychloride, anhydrous acetic acid, etc., a2-halogenopyridinium salt such as 2-chloromethylpyridinium iodide,2-fluoro-1-chloromethylpyridinium iodide, etc.

The condensing agent is used in an amount of about 0.8 to about 5.0moles, preferably about 1.0 to about 3.0 moles, relative to 1 mole ofCompound (II).

In addition, if desired, the reaction may be conducted under thecoexistence of base with the condensing agent.

The “base” is, for example, basic salts such as potassium acetate,sodium acetate, etc., tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc., or 1-hydroxy-1H-benzotriazole (HOBt)monohydrates, etc. The base is used in an amount of about 0.5 to about5.0 moles, preferably about 2.0 to about 3.0 moles, relative to 1 moleof Compound (II).

The present reaction is advantageously carried out using an inertsolvent. Such solvents are, for example, alcohols such as methanol,ethanol, propanol, etc., hydrocarbons such as hexane, cyclohexane,benzene, toluene, xylene, etc., ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide,hexamethylphosphoric triamide, etc., sulfoxides such asdimethylsulfoxide, etc., halogenated carbons such as dichloromethane,chloroform, tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles suchas acetonitrile, propionitrile, etc., acid anhydrides such as aceticanhydride, etc., or a mixed solvent thereof, or the like.

The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 150° C., preferably about 0 to about 100°C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

When R⁵ is an optionally substituted alkyl group, Compound (I) can beproduced according to a method described in the following ReactionScheme 2.

In Reaction Scheme 2, L¹ is a leaving group, and other symbols have thesame meanings as defined above.

The “leaving group” represented by L¹ is, for example, hydroxy, ahalogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.),optionally halogenated C₁₋₅ alkylsulfonyloxy (e.g., methanesulfonyloxy,ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀arylsulfonyloxy, etc.

Compound (Ia) is reacted with an alkylating agent (V) corresponding toCompound (I), if desired, under the presence of base.

The alkylating agent (V) is used in an amount of about 1.0 to about 10.0moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole ofCompound (Ia).

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, etc., or the like.

The base is used in an amount of about 1.0 to about 10.0 moles,preferably about 1.0 to about 2.0 moles, relative to 1 mole of Compound(Ia).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −20 to about 200° C., preferably about 0 to about 150° C.

In addition, Compound (Ib) which is contained in Compound (I), can bealso produced by a method described in the following Reaction Scheme 3.

In Reaction Scheme 3, M is a metal and other symbols have the samemeanings as defined above.

In the formula, an organic metallic Compound (VII) represented by R⁴-Mis commercially available, and further can be also produced by per seknown methods, for example, the method described in ExperimentalChemistry Lecture, 4^(th) Ed., 25 (Japanese Society of Chemistry),Maruzen, Co., Ltd.

As shown in Reaction Scheme 3, Compound (Ib) is obtained by reactingCompound (VI) with the organic metallic Compound (VII).

The organic metallic Compound (VII) is preferably a Grignard reagent oran organic lithium reagent.

Compound (VII) is used in an amount of about 0.8 to about 30 moles,preferably about 1.0 to about 10 moles, relative to 1 mole of Compound(VI).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, hydrocarbonssuch as hexane, cyclohexane, benzene, toluene, xylene, etc., ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., halogenated carbons such as dichloromethane,chloroform, tetrachlorocarbon, 1,2-dichloroethane, etc., or a mixedsolvent thereof, or the like.

The reaction time is usually about 10 minutes to about 24 hours,preferably about 30 minutes to about 5 hours. The reaction temperatureis usually about −100 to about 120° C., preferably about −80 to about60° C.

The product can be used in the next reaction as a crude product, or canbe isolated from the reaction mixture according to a conventionalmethod, and easily purified by conventional means of separation (e.g.,recrystallization, distillation, chromatography, etc.).

Compound (Ic) and Compound (Id), which are contained in Compound (I),can be produced by each method described in the following ReactionScheme 4, respectively, from Compound (Ib) produced by the methoddescribed in Reaction Scheme 3, etc.

In Reaction Scheme 4, each symbol has the same meaning as defined above.

Compound (Ib) is subjected to known acylation, etherification,amination, halogenation, alkylation, or a combination of two or more ofthese reactions, to produce Compound (Ic).

For example, when R³ is alkoxy (e.g., methoxy, ethoxy, phenoxy, etc.),Compound (Ib) is reacted with alcohol (e.g., methanol, ethanol, phenol,etc.) under the presence of acid catalyst to give Compound (Ic).

The “acid catalyst” is, for example, organic acids such as formic acid,acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc., mineralacids such as sulfuric acid, hydrochloric acid, hydrobromic acid, etc.,Lewis acids such as zinc chloride, etc.

The alcohol is used in an amount of about 0.8 moles to excessive amount,relative to 1 mole of Compound (Ib). The acid catalyst is usedrespectively in an amount of about 0.1 to about 100 moles, preferablyabout 0.1 to about 50 moles, relative to 1 mole of Compound (Ib).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction.

Such solvents are not particularly limited if the reaction proceeds, andinclude, for example, hydrocarbons such as hexane, cyclohexane, benzene,toluene, xylene, etc., ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphorictriamide, etc., sulfoxides such as dimethylsulfoxide, etc., halogenatedcarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., or a mixed solvent thereof, or the like.

The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 12 hours. The reaction temperatureis usually about 0 to about 200° C., preferably about 25 to about 100°C.

The product can be used in the next reaction as the reaction solutionitself or the crude product, or can be isolated from the reactionmixture according to a conventional method, and easily purified byconventional means of separation (e.g., recrystallization, distillation,chromatography, etc.).

In addition, Compound (Id) can be produced by subjecting Compound (Ib)to reductive dehydration.

The reductive dehydration is, for example, per se known catalyticreduction, a method in which an organosilyl reagent (an alkylsilanereagent, etc.) is used, etc.

In the catalytic reduction, Compound (Ib) is reacted with a metalcatalyst under hydrogen atmosphere to produce Compound (Id). A suitableacid catalyst may be added, if desired.

The “metal catalyst” is, for example, Raney nickel, platinum oxide,metal palladium, palladium on activated carbon, etc. The “metalcatalyst” is used respectively in an amount of usually about 0.1 toabout 1000% by weight, preferably about 1 to about 20% by weight,relative to Compound (Ib).

The “acid catalyst” is, for example, organic acids such as formic acid,acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc., mineralacids such as sulfuric acid, hydrochloric acid, hydrobromic acid, etc.The “acid catalyst” is used respectively in an amount of about 0.1 toexcessive amount, relative to 1 mole of Compound (Ib).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., organic acids suchas acetic acid, etc., water, etc., or a mixed solvent thereof, or thelike. The hydrogen pressure is usually about 1 to about 100 atm.,preferably about 1 to about 5 atm. The reaction time is usually about 30minutes to about 48 hours, preferably about 1 to 24 hours. The reactiontemperature is usually about 0 to about 120° C., preferably about 20 toabout 80° C.

After the catalyst is removed, the product may be isolated from thereaction mixture according to a conventional method, and easily purifiedby conventional means of separation (e.g., recrystallization,distillation, chromatography, etc.).

In the method wherein the organosilyl reagent (alkylsilane reagent) isused, Compound (Id) can be produced by reacting Compound (Ib) with thealkylsilane reagent and an acid.

The alkylsilane reagent is, for example, triethylsilane,phenyldimethylsilane, etc. The “alkylsilane reagent” is usedrespectively in an amount of about 0.8 to about 20 moles, preferablyabout 1 to about 5 moles, relative to 1 mole of Compound (Ib).

The acid is, for example, organic acids such as trifluoroacetic acid,etc. The acid is used respectively in an amount of about 0.1 toexcessive amount, relative to 1 mole of Compound (Ib).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction.

Such solvents are not particularly limited if the reaction proceeds, andinclude, for example, ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., halogenated carbons such asdichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., organic acids such as acetic acid, trifluoroacetic acid, etc., ora mixed solvent thereof, or the like.

The product may be isolated from the reaction mixture according to aconventional method, and easily purified by conventional means ofseparation (e.g., recrystallization, distillation, chromatography,etc.).

When Compound (X) represented by R⁴—H is amine, alcohol, thiol, phenolor thiophenol, Compound (I) corresponding to Compound (X) can be alsoproduced by a method described in the following Reaction Scheme 5.

In Reaction Scheme 5, each symbol has the same meaning as defined above.

Compound (X) represented by R⁴—H is commercially available, and furthercan also be produced by per se known methods.

According to Reaction Scheme 5, Compound (I) is obtained by reactingCompound (IX) and Compound (X) under the presence of acid catalyst orbase.

Compound (X) is used in an amount of about 1 mole to about 50 moles,preferably about 1 to about 5 moles, relative to 1 mole of Compound(IX).

The “acid catalyst” is, for example, organic acids such as formic acid,acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc., mineralacids such as sulfuric acid, hydrochloric acid, hydrobromic acid, etc.,Lewis acids such as zinc chloride, etc.

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, etc., or the like.

The acid catalyst is used in an amount of about 0.1 moles to excessiveamount, preferably about 0.1 to about 50 moles, relative to 1 mole ofCompound (IX).

The base is used in an amount of about 1.0 to 5.0 moles, preferablyabout 1.0 to 2.0 moles, relative to 1 mole of Compound (IX).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, alcoholssuch as methanol, ethanol, propanol, etc., ethers such as diethyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbons suchas benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 10 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually −20 to 200° C., preferably 0 to 150° C.

Mitsunobu reaction (Synthesis, 1981, pp. 1˜27) can be also used in steadof the above-mentioned reaction.

This reaction is carried out by reacting Compound (X) and Compound (IX)wherein L¹ is OH, under the presence of azodicarboxylates (e.g.,diethylazodicarboxylate, etc.) and phosphines (e.g., triphenylphosphine,tributylphosphine, etc.).

Compound (X) is used in an amount of about 1.0 to 5.0 moles, preferablyabout 1.0 to 2.0 moles, relative to 1 mole of Compound (IX).

The “azodicarboxylates” and the “phosphines” are used in an amount ofabout 1.0 to 5.0 moles, preferably about 1.0 to 2.0 moles, respectively,relative to 1 mole of Compound (IX).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually 5 minutes to 48 hours, preferably 30minutes to 24 hours. The reaction temperature is usually −20 to 200° C.,preferably 0 to 100° C. The product can be used in the next reaction asa reaction solution as is or a crude product, or can be isolated fromthe reaction mixture according to a conventional method, and easilypurified by conventional means of separation (e.g., recrystallization,distillation, chromatography, etc.).

When R⁴ is an optionally substituted amino group, Compound (Id) which iscontained in Compound (I), can also be produced by reductive aminationdescribed in the following Reaction Scheme 6.

In Reaction Scheme 6, R⁴ is an optionally substituted amino group, andother symbols have the same meanings as defined above.

Compound (Id) is produced by condensing Compound (VI) and Compound (X)which is amine and reducing it by a reducing agent.

Compound (X) is used in an amount of about 1.0 to about 5.0 moles,preferably about 1.0 to about 2.0 moles, relative to 1 mole of Compound(VI).

The “reducing agent” is, for example, metal hydrides such as sodiumborohydride, sodium cyanoborohydride, lithium aluminum hydride, etc.,boranes such as borane tetrahydrofuran complex, etc., hydrosilanes suchas triethylsilane, or formic acid, etc. Further acid catalyst may beadded with the reducing agent, if desired. The acid catalyst is, forexample, mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, etc., sulfonic acids such as methanesulfonic acid,p-toluenesulfonic acid, etc., organic acids such as acetic acid,propionic acid, trifluoroacetic acid, etc., Lewis acids such as zincchloride, aluminum chloride, etc.

The “reducing agent” is used in an amount of about 0.25 to about 5.0moles, preferably about 0.5 to about 2.0 moles respectively, relative to1 mole of Compound (VI).

The amount of the acid catalyst used is, for example, usually about 1 toabout 100 moles, preferably about 1 to about 20 moles, relative to 1mole of Compound (VI) when mineral acids are used.

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., or a mixed solvent thereof, or the like.

The reaction time is usually about 5 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 200° C., preferably about 0 to about 100°C.

This reaction is also carried out by condensation of Compound (VI) andCompound (X), followed by catalytic hydrogenation under hydrogenatmosphere under the coexistence of various catalysts, instead ofreduction by reducing agent. The catalyst to be used is, for example,platinum oxide, platinum on activated carbon, palladium on activatedcarbon, nickel, copper-chrome oxide, rhodium, cobalt, ruthenium, etc.The catalyst is used in an amount of about 0.1 to about 1000% by weight,preferably about 1 to about 1000% by weight, relative to Compound (VI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, water, etc., or a mixedsolvent thereof, or the like.

The reaction time is usually about 30 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about 0 to about 120° C., preferably about 20 to about 80° C.

The product may be isolated from the reaction mixture according to aconventional method, and easily purified by conventional means ofseparation (e.g., recrystallization, distillation, chromatography,etc.).

The following compounds which are contained in Compound (I) (Ie to Ik)are produced by a method described in the following Reaction Scheme 7from Compound (I).

In Reaction Scheme 7, P′ is a protective group of hydroxyl group, R¹⁵ isan optionally substituted alkyl group (methyl, ethyl, phenyl group,etc.), Ar is an optionally substituted aromatic ring (a benzene ring, anaphthalene ring, a pyridine ring, a furan ring, a thiophene ring, animidazole ring, etc.), Ar-hal is aromatic halide, and other symbols havethe same meanings as defined above.

Compound (Ie) having an acyl group as a substituent of R⁷ can beproduced by acylation such as Friedel-Craft reaction, etc. of Compound(I).

This reaction is carried out by reacting Compound (I) and Compound(XXVIII) under the presence of acid catalyst.

Compound (XXVIII) is used in an amount of about 1 mole to about 20moles, preferably about 1 to about 5 moles, relative to 1 mole ofCompound (I).

The “acid catalyst” is, for example, aluminum chloride, iron chloride,stannous chloride, tetrachloro titanium, boron trifluoride diethylether, Lewis acids such as zinc chloride, etc. and polyphosphoric acid,etc. The acid catalyst is used in an amount of about 0.5 moles to about20 moles, preferably about 0.8 to about 5 moles, relative to 1 mole ofCompound (I) when Lewis acid is used. When polyphosphoric acid is used,the acid catalyst is used in an amount of about 5 moles to excessiveamount, relative to 1 mole of Compound (I).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction.

Such solvents are not particularly limited if the reaction proceeds, andinclude, for example, hydrocarbons such as hexane, cyclohexane, benzene,toluene, xylene, etc., halogenated carbons such as dichloromethane,chloroform, tetrachlorocarbon, 1,2-dichloroethane, etc., carbondisulfide or mixed solvent thereof, or the like.

The reaction time is usually 10 minutes to 48 hours, preferably 30minutes to 12 hours. The reaction temperature is usually −70 to 150° C.,preferably −20 to 100° C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (Ig) having a bromo group as a substituent of R⁷ can beproduced by reacting Compound (I) and brominating reagent.

The “brominating reagent” is, for example, bromine adducts such asbromine, N-bromosuccinimide, copper bromide, benzyltrimethylammoniumtribromide like, etc. The brominating reagent is used in an amount ofabout 0.5 moles to about 10 moles, preferably about 1 to about 3 moles,relative to 1 mole of Compound (I).

The present reaction is carried out under the presence of base or Lewisacid or iron, if desired.

The “base” is, for example, basic salts such as sodium carbonate,calcium carbonate, cecium carbonate, sodium hydrogen carbonate, sodiumacetate, potassium acetate, etc., aromatic amines such as pyridine,lutidine, etc., tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc.

The base is used in an amount of about 0.8 to about 10 moles, relativeto 1 mole of Compound (I).

The “Lewis acid” is, for example, aluminum chloride, iron chloride,stannous chloride, tetrachloro titanium, boron trifluoride diethylether, etc. Lewis acid is used in an amount of about 0.01 to about 2moles, relative to 1 mole of Compound (I).

The “iron” is used, for example, in an amount of about 0.01 to about 2moles, relative to 1 mole of Compound (I).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, carbon disulfide, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform,tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such asacetonitrile, propionitrile, etc., sulfoxides such as dimethylsulfoxide,etc., organic acids such as acetic acid, propionic acid, etc.,nitroalkanes such as nitromethane, etc., or a mixed solvent thereof, orthe like.

The reaction temperature is usually −20 to 200° C., preferably 0 to 100°C. The reaction time is usually about 5 minutes to about 24 hours,preferably about 10 minutes to about 5 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (If) having formyl group as a substituent of R⁷ can be producedby per se known methods, for example, the method described in Journal ofOrganic Chemistry, Vol. 49, 409 (1984), Journal of the Indian ChemicalSociety, Vol. 36, pp. 76 (1959), etc., or analogous methods thereto.

Compound (Ih) having boric acid as a substituent of R⁷ is produced bytreating Compound (Ig) with lithium reagent or Grignard reagent,followed by reacting with boric acid ester (XXIX).

The “lithium reagent” is, for example, alkyl lithiums such as n-butyllithium, etc. The lithium reagent is used in an amount of about 0.8 toabout 5.0 moles, preferably about 1.0 to about 3.0 moles, relative to 1mole of Compound (Ig).

The “Grignard reagent” is, for example, magnesium, etc. Magnesium, etc.are used in an amount of about 0.8 to about 5.0 moles, preferably about1.0 to about 2.0 moles, relative to 1 mole of Compound (Ig).

The “boric acid ester” is, for example, trimethylboric acid ester,triisopropylboric acid ester, etc. The boric acid ester is used in anamount of about 0.9 to about 30 moles, preferably about 0.9 to about 15moles, relative to 1 mole of Compound (Ig).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., hydrocarbons such as benzene, toluene, carbon disulfide,cyclohexane, hexane, etc., or a mixed solvent thereof, or the like.

The reaction temperature is usually −100 to 120° C., preferably −80 to70° C. The reaction time is usually about 5 minutes to about 24 hours,preferably about 10 minutes to about 5 hours.

In the present reactions, Compound (Ih) can be obtained by treating withacid (for example, hydrogen chloride, hydrochloric acid, sulfuric acid,acetic acid, etc.), if necessary.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (Ii) having an aromatic ring (a benzene ring, a naphthalenering, a pyridine ring, a furan ring, a thiophene ring, an imidazolering, etc.) as a substituent of R⁷, can be produced by reacting Compound(Ig) and aromatic boronic acid (XXX), in a solvent under basic conditionunder the presence of a transitional metal catalyst.

The “aromatic boronic acid (XXX)” is used in an amount of about 0.5 toabout 10 moles, preferably about 0.9 to about 3 moles, relative to 1mole of Compound (Ig).

The “base” is for example, carbonate of alkali metal or alkali earthmetal (for example, sodium carbonate, potassium carbonate, etc.),hydrogen carbonate of alkali metal or alkali earth metal (for example,sodium hydrogen carbonate, potassium hydrogen carbonate, etc.),hydroxide of alkali metal or alkali earth metal (for example, sodiumhydroxide, potassium hydroxide, etc.), triethylamine,4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylenediamine,4-methylmorpholine, etc.

The “transitional metal catalyst” is, for example, a palladium catalyst[for example, tetrakis(triphenylphosphine)palladium,1,1-bis(diphenylphosphino)ferrocene dichloropalladium,dichlorobis(triphenylphosphine)palladium, etc.], etc. The transitionalmetal catalyst is used in an amount of about 0.001 to about 3 moles,preferably about 0.02 to about 0.2 moles, relative to 1 mole of Compound(Ig).

The solvent is, for example, ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., alcoholssuch as methanol, ethanol, propanol, etc., hydrocarbons such as benzene,toluene, carbon disulfide, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., water or mixed solventthereof, or the like.

The reaction temperature is usually 0 to 250° C., preferably 50 to 150°C. The reaction time is usually about 5 minutes to about 48 hours,preferably about 30 minutes to about 24 hours.

In the present reaction, the reaction time can be shortened usingmicrowave reactor, etc.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

In addition, Compound (Ii) can be also produced by reacting Compound(Ih) and aromatic halide in a solvent under basic condition under thepresence of a transitional metal catalyst.

The “aromatic halide” is used in an amount of about 0.5 to about 10moles, preferably about 0.9 to about 3 moles, relative to 1 mole ofCompound (Ih).

The “base” is for example, carbonate of alkali metal or alkali earthmetal (for example, sodium carbonate, potassium carbonate, etc.),hydrogen carbonate of alkali metal or alkali earth metal (for example,sodium hydrogen carbonate, potassium hydrogen carbonate, etc.),hydroxide of alkali metal or alkali earth metal (for example, sodiumhydroxide, potassium hydroxide, etc.), triethylamine,4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylenediamine,4-methylmorpholine, etc.

The “transitional metal catalyst” is, for example, a palladium catalyst[for example, tetrakis(triphenylphosphine)palladium,1,1-bis(diphenylphosphino)ferrocene dichloropalladium,dichlorobis(triphenylphosphine)palladium, etc.], etc. The transitionalmetal catalyst is used in an amount of about 0.001 to about 3 moles,preferably about 0.02 to about 0.2 moles, relative to 1 mole of Compound(Ih).

The solvent is, for example, ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., alcoholssuch as methanol, ethanol, propanol, etc., hydrocarbons such as benzene,toluene, carbon disulfide, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., water or mixed solventthereof, or the like.

The reaction temperature is usually 0 to 250° C., preferably 50 to 150°C. The reaction time is usually about 5 minutes to about 48 hours,preferably about 30 minutes to about 24 hours.

In the present reaction, the reaction time can be shortened usingmicrowave reactor, etc.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (Ij) having hydroxylated hydrocarbon group as a substituent ofR⁷ is produced by reacting Compound (If) and organic metallic Compound(LV) represented by R¹⁵-M.

The organic metallic Compound (LV) represented by R¹⁵-M is commerciallyavailable, and further can be also produced by per se known methods, forexample, the method described in Experimental Chemistry Lecture, 4^(th)Ed., 25 (Japanese Society of Chemistry), Maruzen, Co., Ltd.

The organic metallic Compound (LV) is preferably a Grignard reagent oran organic lithium reagent.

The organic metallic Compound (LV) is used in an amount of about 0.8 toabout 30 moles, preferably about 1.0 to about 10 moles, relative to 1mole of Compound (If).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, hydrocarbonssuch as hexane, cyclohexane, benzene, toluene, xylene, etc., ethers suchas diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., halogenated carbons such as dichloromethane,chloroform, tetrachlorocarbon, 1,2-dichloroethane, etc., or a mixedsolvent thereof, or the like.

The reaction time is usually about 10 minutes to about 24 hours,preferably about 30 minutes to about 5 hours. The reaction temperatureis usually about −100 to about 120° C., preferably about −80 to about60° C.

The product can be used in the next reaction as a crude product, or canbe isolated from the reaction mixture according to a conventionalmethod, and easily purified by conventional means of separation (e.g.,recrystallization, distillation, chromatography, etc.).

In addition, Compound (Ij) can be also produced by reducing Compound(Ie).

The “reducing agent” is, for example, metal hydrides such as aluminumhydride, isobutylaluminum hydride, etc., complex metal hydrides such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,etc. The reducing agent is used in an amount of about 0.3 to about 5.0moles, preferably about 0.5 to about 2.0 moles, relative to 1 mole ofCompound (Ie).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, carbon disulfide, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform,tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such asacetonitrile, propionitrile, etc., sulfoxides such as dimethylsulfoxide,etc., or a mixed solvent thereof, or the like.

The reaction temperature is usually −40 to 120° C., preferably −20 to80° C. The reaction time is usually about 5 minutes to about 24 hours,preferably about 10 minutes to about 5 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (Ie) can be also produced by reacting oxidizing Compound (Ij).

The “oxidizing agent” is, for example, anhydrous chromic acid, chromatessuch as pyridinium chlorochromate, pyridinium dichromate, sodiumbichromate, potassium bichromate, etc., periodates such as para-periodicacid, meta-periodic acid, sodium meta-periodate, etc., metal oxides suchas manganese dioxide, silver oxide, lead oxide, etc. Combination withsulfoxides such as dimethylsulfoxide, etc. and a dehydrating agent suchas oxalyl chloride, N,N-dicyclohexylcarbodiimide, etc. may be used. Theoxidizing agent is used in an amount of about 1 to about 30 moles,preferably about 1 to about 5 moles, relative to 1 mole of Compound(Ij).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, carbon disulfide, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform,tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such asacetonitrile, propionitrile, etc., sulfoxides such as dimethylsulfoxide,etc., water or mixed solvent thereof, or the like.

The reaction temperature is usually −90 to 200° C., preferably −80 to120° C. The reaction time is usually about 5 minutes to about 48 hours,preferably about 10 minutes to about 16 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (Ik) having a hydroxylated aralkyl group (R¹⁵CH₂) as asubstituent of R⁷ can be produced by subjecting Compound (Ij) toreductive dehydration.

The reductive dehydration is, for example, per se known catalyticreduction, a method in which an organosilyl reagent (an alkylsilanereagent, etc.) is used, etc.

In the catalytic reduction, Compound (Ij) is reacted with a metalcatalyst under hydrogen atmosphere to produce Compound (Ik). A suitableacid catalyst may be added, if desired.

The “metal catalyst” is, for example, Raney nickel, platinum oxide,metal palladium, palladium on activated carbon, etc. The “metalcatalyst” is respectively used in an amount of usually about 0.1 toabout 1000% by weight, preferably about 1 to about 20% by weight,relative to Compound (Ij).

The “acid catalyst” is, for example, organic acids such as formic acid,acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc., mineralacids such as sulfuric acid, hydrochloric acid, hydrobromic acid, etc.The “acid catalyst” is used respectively in an amount of about 0.1 toexcessive amount, relative to 1 mole of Compound (Ij).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., organic acids suchas acetic acid, water, etc., or a mixed solvent thereof, or the like.The hydrogen pressure is usually about 1 to about 100 atm., preferablyabout 1 to about 5 atm. The reaction time is usually about 30 minutes toabout 48 hours, preferably about 1 to 24 hours. The reaction temperatureis usually about 0 to about 120° C., preferably about 20 to about 80° C.

After the catalyst is removed, the product may be isolated from thereaction mixture according to a conventional method, and easily purifiedby conventional means of separation (e.g., recrystallization,distillation, chromatography, etc.).

In the method wherein organosilyl reagent (alkylsilane reagent) is used,Compound (Ik) can be produced by reacting Compound (Ij) with analkylsilane reagent and an acid.

The alkylsilane reagent is, for example, triethylsilane,phenyldimethylsilane, etc. The “alkylsilane reagent” is usedrespectively in an amount of about 0.8 to about 20 moles, preferablyabout 1 to about 5 moles, relative to 1 mole of Compound (Ij).

The acid is, for example, organic acids such as trifluoroacetic acid,etc. The acid is used respectively in an amount of about 0.1 toexcessive amount, relative to 1 mole of Compound (Ij).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, ethers suchas diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,halogenated carbons such as dichloromethane, chloroform,tetrachlorocarbon, 1,2-dichloroethane, etc., organic acids such asacetic acid, trifluoroacetic acid, etc., or a mixed solvent thereof, orthe like.

The product may be isolated from the reaction mixture according to aconventional method, and easily purified by conventional means ofseparation (e.g., recrystallization, distillation, chromatography,etc.).

The above-mentioned Compound (II) is produced by, per se known methods,for example, the method described in JP-A-1993-140142, or analogousmethods thereto, etc.

In addition, Compound (IIa), a dihydrobenzofuran derivative which iscontained in Compound (II), can be produced by per se known methods, forexample, the method described in Reaction Scheme 8 or Reaction Scheme 9below which is described in WO2003-004485, etc. Further, other compoundswhich are contained in Compound (II), can be also produced by knownmethod from Compound (IIa), if necessary.

In Reaction Scheme 8, R⁹ is a hydrogen atom or a group formed bydeducting one methylene from R¹. R¹⁰ is a group formed by deducting onemethylene from R⁵. Other symbols have the same meanings as definedabove.

Obtained Compound (IIa) can be subjected to alkylation, if necessary.The alkylation can be carried out by reacting Compound (IIa) with analkylating agent corresponding to the objective, compound (II), ifdesired, under the presence of base.

The alkylating agent is used in an amount of about 1.0 to about 5.0moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole ofCompound (IIa).

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, etc., or the like.

The base is used in an amount of about 1.0 to about 5.0 moles,preferably about 1.0 to about 2.0 moles, relative to 1 mole of Compound(IIa).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 30 minutes to about 48 hours,preferably about 1 hour to about 24 hours. The reaction temperature isusually about −20 to about 200° C., preferably about 0 to about 150° C.

Alternatively, a method can be used wherein Compound (IIa) and Compound(XVI) are reacted, if desired, under the presence of base or acid toproduce acylamide, which is reduced by a reducing agent.

Compound (XVI) is used in an amount of about 1.0 to 5.0 moles,preferably about 1.0 to 2.0 moles, relative to 1 mole of Compound (IIa).

The “base” is, for example, organic bases such as triethylamine,pyridine, etc.

The “acid” is, for example, methanesulfonic acid, p-toluenesulfonicacid, camphor-sulfonic acid, etc.

The “base” is used in an amount of about 0.1 to 10 equivalents,preferably 0.8 to 2 equivalents, relative to Compound (IIa).

The “acid” is used in an amount of about 0.1 to 10 equivalents,preferably 0.8 to 3 equivalents, relative to Compound (IIa).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, ethers suchas diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc., amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., nitrogen-containingaromatic hydrocarbons such as pyridine, lutidine, quinoline, etc., or amixed solvent thereof, or the like. The reaction temperature is about−20 to 150° C., preferably 0 to 100° C. The reaction time is usually 5minutes to 24 hours, preferably 10 minutes to 5 hours.

Thus obtained acylamide can be used in the next reaction as a reactionsolution as is or a crude product, or can be isolated from the reactionmixture according to a conventional method, and easily purified byconventional means of separation (e.g., recrystallization, distillation,chromatography, etc.).

The reducing agent is, for example, metal hydrides such as sodiumborohydride, lithium aluminum hydride, etc., boranes such as boranetetrahydrofuran complex, etc.

In addition, an acid catalyst may be added with the reducing agent, ifdesired. The acid catalyst is, for example, Lewis acids such astrifluoroborane diethyl ether complex, aluminum chloride, etc.

The reducing agent is used respectively in an amount of about 0.25 toabout 10 moles, preferably about 0.5 to about 5 moles, relative to 1mole of acylamide.

The Lewis acids are used respectively in an amount of about 0.25 toabout 10 moles, preferably about 0.5 to about 5 moles, relative to 1mole of acylamide.

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, water, etc., or a mixed solvent thereof,or the like.

The reaction time is usually about 30 minutes to about 24 hours,preferably about 1 hour to about 16 hours. The reaction temperature isusually about 0 to about 150° C., preferably about 20 to about 100° C.

Thus obtained product (II) can be used in the method described inReaction Scheme (I) as a reaction solution as is or a crude product, canbe isolated from the reaction mixture according to a conventionalmethod, and easily purified by conventional means of separation (e.g.,recrystallization, distillation, chromatography, etc.).

In Reaction Scheme 9, P′ is a protective group of hydroxyl group, andother symbols have the same meanings as defined above.

Compound (XVII) is produced by subjecting Compound (XII) to addition ofa protective group which is generally used in the peptide chemistry,etc.

Compound (IIa) is provided to the next reaction, if necessary, as in themethod described in Reaction Scheme 8.

In addition, Compounds (IIb), (IIc), and (IId) which are contained inCompound (II), are also produced by a method described in the followingReaction Scheme 10.

In Reaction Scheme 10, hal is a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.), and other symbols have the same meanings asdefined above.

Compound (XXIII) can be produced by reacting Compound (XXI) withCompound (XXII) under acidic condition.

Compound (XXI) is commercially available, and further can be alsoproduced by per se known methods, for example, the method described inExperimental Chemistry Lecture 20, 4^(th) Ed., (Japanese Society ofChemistry), 111 to 185, Maruzen, Co., Ltd. and analogous methodsthereto.

Compound (XXII) is commercially available, and further can be alsoproduced by per se known methods and analogous methods thereto.

The “acid” is, for example, Lewis acids such as aluminum chloride, ironchloride, stannous chloride, tetrachloro titanium, boron trifluoridediethyl ether, etc., mineral acids such as polyphosphoric acid, sulfuricacid, etc., organic acids such as trifluoroacetic acid, methanesulfonicacid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.

The acid is used in an amount of, for example, usually about 0.5 toabout 100 moles, preferably about 10 to about 50 moles, relative to 1mole of Compound (XXI) when mineral acids are used, and usually about0.1 to about 20 moles, preferably about 0.1 to about 5 moles, relativeto 1 mole of Compound (XXI) when sulfonic acids are used.

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds. For example, when mineral acids areused, the solvent is, preferably a mixed solvent of water and organicsolvents such as saturated hydrocarbons such as cyclohexane, hexane,etc., aromatic hydrocarbons such as benzene, toluene, xylene, etc.,ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethylether, diisopropyl ether, etc., halogenated hydrocarbons such asdichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., or water.

The reaction time is usually about 30 minutes to about 24 hours,preferably about 30 minutes to about 6 hours. The reaction temperatureis usually about −78 to about 200° C., preferably about −20 to about150° C.

The product can be used in the next reaction as a crude product, or canbe isolated from the reaction mixture according to a conventionalmethod, and easily purified by conventional means of separation (e.g.,recrystallization, distillation, chromatography, etc.).

Compound (XXIV) is produced by reducing Compound (XXIII).

The reducing agent is, for example, metal hydrides such as aluminumhydride, diisobutylaluminum hydride, etc., complex metal hydrides suchas sodium borohydride, lithium borohydride, lithium aluminum hydride,sodium aluminum bis(2-methoxyethoxy) hydride, etc., borane complexessuch as borane tetrahydrofuran complex, borane dimethylsulfide, etc.,alkylboranes such as thexylborane, diamylborane, etc., diborane, etc.

In addition, an acid catalyst may be added with the reducing agent, ifdesired. The acid catalyst is, for example, Lewis acids such astrifluoroborane diethyl ether complex, aluminum chloride, etc.

The reducing agent is used respectively in an amount of about 0.25 toabout 10 moles, preferably about 0.5 to about 5 moles, relative to 1mole of Compound (XXIII).

The Lewis acids are used respectively in an amount of about 0.25 toabout 10 moles, preferably about 0.5 to about 5 moles, relative to 1mole of Compound (XXIII).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, water, etc., or a mixed solvent thereof,or the like.

The reaction time is usually about 30 minutes to about 24 hours,preferably about 1 hour to about 16 hours. The reaction temperature isusually about 0 to about 150° C., preferably about 20 to about 100° C.

Thus obtained product (XXIV) can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation, such as recrystallization, distillation,chromatography, etc.

Compound (XXV) is produced by converting Compound (XXIV) (e.g., thecompound in which L¹ is hydroxy) to sulfonate or halide, and subjectingit to cyclization. The sulfonate compound is synthesized by reactingCompound (XXIV) and corresponding sulfonyl chloride compound (forexample, benzenesulfonyl chloride, toluenesulfonyl chloride, C₁₋₄alkylsulfonyl chloride, for example, methanesulfonyl chloride, etc.)under the presence of base.

The sulfonyl chloride compound is used respectively in an amount ofabout 1.0 to about 10 moles, preferably about 1.0 to about 5 moles,relative to 1 mole of Compound (XXIV). The base is, for example, organicbases such as triethylamine, pyridine, etc.

The base is used respectively in an amount of about 1.0 to about 50moles, preferably about 1.0 to about 20 moles, relative to 1 mole ofCompound (XXIV).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction.

Such solvents are not particularly limited if the reaction proceeds, andinclude, for example, alcohols such as methanol, ethanol, propanol,etc., ethers such as diethyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., nitriles such as acetonitrile, propionitrile, etc., sulfoxidessuch as dimethylsulfoxide, etc., nitrogen-containing aromatichydrocarbons such as pyridine, lutidine, quinoline, etc., or a mixedsolvent thereof, or the like. The reaction temperature is about −78 to150° C., preferably −30 to 100° C. The reaction time is usually 5minutes to 24 hours, preferably 10 minutes to 5 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

The halide is synthesized by reacting Compound (XXIV) and a halogenatingagent (for example, phosphorus halide such as phosphorus trichloride,phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide,etc., halogen, thionyl chloride, etc.).

The halogenating agent is used in an amount of about 1.0 to about 100moles, preferably about 1.0 to about 10 moles, relative to 1 mole ofCompound (XXIV). The present reaction is advantageously carried outwithout a solvent or with a solvent inert to the reaction. Such solventsare not particularly limited if the reaction proceeds, and include, forexample, ethers such as diethyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., nitriles such as acetonitrile, propionitrile, etc., sulfoxidessuch as dimethylsulfoxide, etc., or a mixed solvent thereof, or thelike. The reaction temperature is about 0 to 200° C., preferably 10 to100° C. The reaction time is usually 10 minutes to 24 hours, preferably10 minutes to 5 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XXV) is also synthesized by subjecting thus obtained sulfonatecompound or halide to cyclization under the presence of base. The baseis, for example, organic bases such as triethylamine, pyridine, etc.

The base is used respectively in an amount of about 1.0 to about 50moles, preferably about 1.0 to about 20 moles, relative to 1 mole of thesulfonate compound or halide. The present reaction is advantageouslycarried out without a solvent or with a solvent inert to the reaction.Such solvents are not particularly limited if the reaction proceeds, andinclude, for example, alcohols such as methanol, ethanol, propanol,etc., ethers such as diethyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., hydrocarbons such as benzene, toluene,cyclohexane, hexane, etc., amides such as N,N-dimethylformamide,N,N-dimethylacetamide, etc., halogenated hydrocarbons such asdichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., nitriles such as acetonitrile, propionitrile, etc., esters such asethyl acetate, etc., water or mixed solvent thereof, or the like. Thereaction temperature is about −10 to 250° C., preferably 0 to 120° C.The reaction time is usually 10 minutes to 6 hours, preferably 10minutes to 2 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Alternatively, Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can bealso used.

In this reaction, Compound (XXIV) in which L¹ is OH, is subjected tointra-molecular cyclization under the presence of azodicarboxylates(e.g., diethyl azodicarboxylate, etc.) and phosphines (e.g.,triphenylphosphine, tributylphosphine, etc.) to give Compound (XXV).

The “azodicarboxylates” and the “phosphines” are used respectively in anamount of about 1.0 to 5.0 moles, preferably about 1.0 to 2.0 moles,relative to 1 mole of Compound (XXIV).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually 5 minutes to 48 hours, preferably 30minutes to 24 hours. The reaction temperature is usually −20 to 200° C.,preferably 0 to 100° C.

In addition, Compound (XXVI) can be synthesized by nitrating Compound(XXV). The nitrating agent is, for example, mixed acid, acetyl nitrate,fuming nitric acid, potassium nitrate, ammonium nitrate, nitroniumtetrafluoroborate, nitronium trifluoromethanesulfonate, etc. Thenitrating agent is used in an amount of about 1.0 to about 50 moles,preferably about 1.0 to about 10 moles, relative to 1 mole of Compound(XXV). The present reaction is advantageously carried out without asolvent or with a solvent inert to the reaction. Such solvents are notparticularly limited if the reaction proceeds, and include, for example,organic acids such as acetic acid, trifluoroacetic acid, etc., acidanhydride such as acetic anhydride, trifluoroacetic anhydride, etc.,mineral acids such as sulfuric acid, nitric acid, etc., saturatedhydrocarbons such as hexane, cyclohexane, etc., halogenated carbons suchas dichloromethane, chloroform, tetrachlorocarbon, 1,2-dichloroethane,etc., or a mixed solvent thereof, or the like.

The reaction time is usually about 10 minutes to about 24 hours,preferably about 10 minutes to about 16 hours. The reaction temperatureis usually about −10 to about 200° C., preferably about −10 to about120° C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (IIb) is produced by reducing Compound (XXVI).

The reducing agent which is used in the reduction is, for example, metalhydrides such as aluminum hydride, diisobutylaluminum hydride, etc.,complex metal hydrides such as sodium borohydride, lithium aluminumhydride, etc., borane complexes such as borane tetrahydrofuran complex,borane dimethylsulfide, etc., alkylboranes such as thexylborane,diamylborane, etc., diborane, or metals such as zinc, aluminum, tin,iron, etc., alkali metals (sodium, lithium, etc.)/liquid ammonia (batchreduction), etc.

Further, the hydrogenating catalyst is, for example, palladium carbon,platinum oxide, Raney nickel, Raney cobalt, etc. The hydrogen source is,for example, formic acid, ammonium formate, hydrazine, etc. in additionto gas-phase hydrogen.

The “reducing agent” is used in an amount of, for example, about 1.0 toabout 10 moles, preferably about 1.0 to about 3.0 moles, relative to 1mole of Compound (XXVI) when metal hydrides or complex metal hydride isused, about 1.0 to about 10 moles, preferably about 1.0 to about 5.0moles when borane complexes, alkylboranes or diborane is used, and about1.0 to about 20 equivalents, preferably about 1.0 to about 5.0equivalents when metals or alkali metals are used to 1 mole of Compound(XXVI). In case of hydrogenation, the catalyst such as palladium carbon,platinum oxide, Raney nickel, Raney cobalt, etc. is used in an amount ofabout 5 to 1000% by weight, preferably about 10 to 300% by weight,relative to Compound (XXVI). When the hydrogen source other thangas-phase hydrogen is used, it is used in an amount of about 1.0 toabout 20 moles, preferably about 2.0 to about 10 moles, relative to 1mole of Compound (XXVI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., formic acid, organicacids such as acetic acid, water, etc., or a mixed solvent thereof, orthe like. When the catalyst of Raney nickel or Raney cobalt is used,amines such as ammonia, etc. may be further added to inhibit reversereaction.

The reaction time is varied depending on kinds or amount of reducingagent, or activity or amount of catalyst, but usually about 1 hour toabout 100 hours, preferably about 1 hour to about 50 hours. The reactiontemperature is usually about 0 to about 150° C., preferably about 20 toabout 100° C. When a hydrogenation catalyst is used, hydrogen pressureis usually 1 to 100 atm.

Thus obtained product (IIb) can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XXVII) is produced by reacting Compound (XXV) and ahalogenating reagent.

The “halogenating reagent” is, for example, chlorine, bromine, iodine,imides such as N-chlorosuccinimide or N-bromosuccinimide, etc., halogenadducts such as benzyltrimethylammonium tribromide, etc. The“halogenating reagent” is used in an amount of about 0.8 to about 5.0moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole ofCompound (XXV).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., organic acids such asacetic acid, propionic acid, etc., nitroalkanes such as nitromethane,etc., aromatic amines such as pyridine, lutidine, quinoline, etc., or amixed solvent thereof, or the like.

The present reaction is carried out under the presence of base or Lewisacid or iron, if desired.

The “base” is, for example, basic salts such as sodium carbonate,calcium carbonate, cecium carbonate, sodium hydrogen carbonate, sodiumacetate, potassium acetate, etc., aromatic amines such as pyridine,lutidine, etc., tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc. The base is used in an amount of about 0.8 toabout 10 moles, relative to 1 mole of Compound (XXV).

The “Lewis acid” is, for example, iron chloride, aluminum chloride,boron trifluoride, etc. The Lewis acid is used in an amount of about0.01 to about 5 moles, relative to 1 mole of Compound (XXV).

The “iron” is used in an amount of about 0.01 to about moles, relativeto 1 mole of Compound (XXV).

The reaction temperature is usually about −50 to about 150° C.,preferably about −20 to about 100° C. The reaction time is usually about5 minutes to about 24 hours, preferably about 10 minutes to about 12hours.

In addition, when a halogen atom is substituted on ring A of Compound(XXI), Compound (XXVII) can be produced without halogenation.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (IIc) is produced by reacting Compound (XXVII) and benzylamine,if desired, under the presence of base. If necessary, a catalyst such ascopper, copper salt, etc. may be used, or a catalyst such as palladiumor nickel, etc. and a ligand (for example, phosphine or pyridines, etc.)may be also used according to the method described in Chemistry Letters,1983, pp. 927-928.

The benzylamine is used in an amount of about 0.8 to about 10.0 moles,preferably about 1.0 to about 5.0 moles, relative to 1 mole of Compound(XXVII).

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc., orthe like.

The “base” is used in an amount of about 0.8 to about 10.0 moles,preferably about 1.0 to about 5.0 moles, relative to 1 mole of Compound(XXVII).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The “copper catalyst” is, for example, copper, halogenated copper (CuI,CuBr, CuCl, etc.), copper oxide (CuO), etc. The copper catalyst is usedin an amount of about 0.1 to about 10.0 moles, preferably about 0.5 toabout 2.0 moles, relative to 1 mole of Compound (XXVII).

The “ligand” is preferably phosphines such as trialkylphosphine,triarylphosphine, trialkoxyphosphine, etc. The palladium catalyst is,for example, palladium acetate, palladium chloride,

tetrakis(triphenylphosphine)palladium,bis(dibenzylideneacetone)palladium, etc.

The “phosphine” is used in an amount of about 0.001 to about 10.0 moles,preferably about 0.01 to about 1.0 mole, relative to 1 mole of Compound(XXVII). The palladium catalyst is used in an amount of about 0.001 toabout 5.0 moles, preferably about 0.01 to about 0.5 moles, relative to 1mole of Compound (XXVII).

The reaction time is usually about 30 minutes to about 72 hours,preferably about 1 hour to about 48 hours. The reaction temperature isusually about −20 to about 200° C., preferably about 0 to about 150° C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (IIb) is produced by debenzylation of Compound (IIc). Thedebenzylation is carried out by per se known reaction, for example, themethod described in T. W. Green, Protective Groups in Organic Synthesis,3^(rd) Ed., 1999, Chapter of “Protection for the Amino Group”, etc.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (IId) is produced from Compound (IIb) by the same method asshown in Reaction Scheme 9 in which Compound (II) is produced fromCompound (IIa), if necessary.

When R³ is a hydrogen atom, Compound (IIf) and Compound (IIg) which arecontained in Compound (II), are also produced by a method described inthe following Reaction Scheme 11.

In Reaction Scheme 11, each symbol has the same meaning as definedabove.

Compound (XXXII) is produced by reacting Compound (XXI) and Compound(XXXI), if desired, under the presence of base.

Compound (XXXI) is commercially available, and further can be alsoproduced by per se known methods.

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, etc., or the like.

Compound (XXXI) is used in an amount of about 0.7 to about 5.0 moles,preferably about 1.0 to about 3.0 moles, relative to 1 mole of Compound(XXI).

The base is used in an amount of about 0.8 to about 5.0 moles,preferably about 1.0 to about 3.0 moles, relative to 1 mole of Compound(XXI). Further, if desired, quaternary ammonium salt may be combined andreacted with the base in producing Compound (XXXII). The “quaternaryammonium salt” is, for example, tetrabutylammonium iodide, etc.

The quaternary ammonium salt is used in an amount of about 0.1 to about2.0 moles, preferably about 0.5 to about 1.0 mole, relative to 1 mole ofCompound (XXI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 30 minutes to about 96 hours,preferably about 1 hour to about 72 hours. The reaction temperature isusually about 0 to about 120° C., preferably about 0 to about 60° C.

Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can be also used in steadof the above-mentioned reaction.

This reaction is carried out by reacting Compound (XXI) and Compound(XXXI) in which L¹ is OH under the presence of azodicarboxylates (e.g.,diethyl azodicarboxylate, etc.) and phosphines (e.g.,triphenylphosphine, tributylphosphine, etc.). Compound (XXXI) is used inan amount of about 0.8 to about 5.0 moles, preferably about 1.0 to about3.0 moles, relative to 1 mole of Compound (XXI).

The “azodicarboxylates” and the “phosphines” are used respectively in anamount of about 0.8 to about 5.0 moles, preferably about 1.0 to about3.0 moles, relative to 1 mole of Compound (XXI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 5 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 200° C., preferably about 0 to about 100°C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XXXIII) is produced by subjecting Compound (XXXII) to per seknown cyclization.

For this cyclization, an acid is used.

The “acid” is, for example, Lewis acids such as aluminum chloride, ironchloride, stannous chloride, tetrachloro titanium, boron trifluoridediethyl ether, etc., mineral acids such as polyphosphoric acid, sulfuricacid, etc., organic acids such as trifluoroacetic acid, methanesulfonicacid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.,acidic resin or clay such as zeolite, Amberlite, Montmorillonite, etc.,or the like.

The “acid” is used respectively in an amount of catalytic amount toexcessive amount to Compound (XXXII), preferably about 0.8 to about 5moles, relative to 1 mole of Compound (XXXII). The acidic resin or clayis used in an amount of about 0.1 to 50 grams, preferably 1 to 5 grams,relative to 1 gram of Compound (XXXII).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, ethers suchas diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc., carbondisulfide, nitroalkanes such as nitromethane, etc., nitroaryls such asnitrobenzene, etc., halogenated carbons such as dichloromethane,chloroform, tetrachlorocarbon, 1,2-dichloroethane, 1,2-dichlorobenzene,etc., organic acids such as acetic acid, trifluoroacetic acid, etc., ora mixed solvent thereof, or the like.

The reaction time is usually about 10 minutes to about 96 hours,preferably about 30 minutes to about 16 hours. The reaction temperatureis usually about −70 to about 200° C., preferably about −20 to about150° C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XXXIV) is produced by reducing Compound (XXXIII).

The reduction is carried out by catalytic reduction, a method in whichan organosilyl reagent (an alkylsilane reagent, etc.) is used, etc.

The catalytic reduction is carried out by per se known reaction, forexample, using catalyst such as palladium carbon, etc. under hydrogenatmosphere. After the catalyst is removed, the product can be used inthe next reaction as a reaction solution as is or a crude product, orcan be isolated from the reaction mixture according to a conventionalmethod, and easily purified by conventional means of separation (e.g.,recrystallization, distillation, chromatography, etc.).

In the method wherein organosilyl reagent (alkylsilane reagent) is used,Compound (XXXIV) can be produced by reacting Compound (XXXIII) with analkylsilane reagent and an acid.

The alkylsilane reagent is, for example, triethylsilane,phenyldimethylsilane, etc. The “alkylsilane reagent” is usedrespectively in an amount of about 0.8 to about 20 moles, preferablyabout 1 to about 5 moles, relative to 1 mole of Compound (XXXIII).

The acid is, for example, organic acids such as trifluoroacetic acid,etc. The acid is used respectively in an amount of about 0.1 toexcessive amount, relative to 1 mole of Compound (XXXIII).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction. Such solvents are not particularlylimited if the reaction proceeds, and include, for example, ethers suchas diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.,hydrocarbons such as benzene, toluene, cyclohexane, hexane, etc.,halogenated carbons such as dichloromethane, chloroform,tetrachlorocarbon, 1,2-dichloroethane, etc., organic acids such asacetic acid, trifluoroacetic acid, etc., or a mixed solvent thereof, orthe like.

The product may be isolated from the reaction mixture according to aconventional method, and easily purified by conventional means ofseparation (e.g., recrystallization, distillation, chromatography,etc.).

Compound (XXXV) is produced by reacting Compound (XXXIV) andhalogenating reagent.

The “halogenating reagent” is, for example, chlorine, bromine, iodine,imides such as N-chlorosuccinimide or N-bromosuccinimide, etc., halogenadducts such as benzyltrimethylammonium tribromide, etc., or the like.The halogenating reagent is used in an amount of about 0.8 to about 5.0moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole ofCompound (XXXIV).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., organic acids such asacetic acid, propionic acid, etc., nitroalkanes such as nitromethane,etc., aromatic amines such as pyridine, lutidine, quinoline, etc., or amixed solvent thereof, or the like.

The present reaction is carried out under the presence of base or Lewisacid or iron, if desired.

The “base” is, for example, basic salts such as sodium carbonate,calcium carbonate, cecium carbonate, sodium hydrogen carbonate, sodiumacetate, potassium acetate, etc., aromatic amines such as pyridine,lutidine, etc., tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc. The base is used in an amount of about 0.8 toabout 10 moles, relative to 1 mole of Compound (XXXIV).

The “Lewis acid” is, for example, iron chloride, aluminum chloride,boron trifluoride, etc. The Lewis acid is used in an amount of about0.01 to about 5 moles, relative to 1 mole of Compound (XXXIV).

The “iron” is used in an amount of about 0.01 to about 5 moles, relativeto 1 mole of Compound (XXXIV).

The reaction temperature is usually about −50 to about 150° C.,preferably about −20 to about 100° C. The reaction time is usually about5 minutes to about 24 hours, preferably about 10 minutes to about 12hours. The product can be used in the next reaction as a reactionsolution as is or a crude product, or can be isolated from the reactionmixture according to a conventional method, and easily purified byconventional means of separation (e.g., recrystallization, distillation,chromatography, etc.).

In addition, when a halogen atom is substituted on a benzene ring ofCompound (XXI), Compound (XXXV) can be produced without halogenation.

Compound (XXXVI) is produced by reacting Compound (XXXV) andbenzylamine, if desired, under the presence of base. If necessary, acatalyst such as copper, copper salt, etc. may be used, or a catalystsuch as palladium or nickel, etc. and a ligand (for example, phosphineor pyridines, etc.) may be also used according to the method describedin Chemistry Letters, 1983, pp. 927-928 catalyst.

The benzylamine is used in an amount of about 0.8 to about 10.0 moles,preferably about 1.0 to about 5.0 moles, relative to 1 mole of Compound(XXXV).

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc., orthe like.

The base is used in an amount of about 0.8 to about 10.0 moles,preferably about 1.0 to about 5.0 moles, relative to 1 mole of Compound(XXXV).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, alcohols such as methanol,ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, etc., hydrocarbons such as benzene,toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The copper catalyst is, for example, copper, halogenated copper (CuI,CuBr, CuCl, etc.), copper oxide (CuO), etc.

The copper catalyst is used in an amount of about 0.1 to about 10.0moles, preferably about 0.5 to about 2.0 moles, relative to 1 mole ofCompound (XXXV).

The “ligand” is preferably phosphines such as trialkylphosphine,triarylphosphine, trialkoxyphosphine, etc. The palladium catalyst is,for example, palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,bis(dibenzylideneacetone)palladium, etc. The phosphine is used in anamount of about 0.001 to about 10.0 moles, preferably about 0.01 toabout 1.0 mole, relative to 1 mole of Compound (XXXV). Palladiumcatalyst is used in an amount of about 0.001 to about 5.0 moles,preferably about 0.01 to about 0.5 moles, relative to 1 mole of Compound(XXXV).

The reaction time is usually about 30 minutes to about 72 hours,preferably about 1 hour to about 48 hours. The reaction temperature isusually about −20 to about 200° C., preferably about 0 to about 150° C.The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (IIf) is produced by debenzylation of Compound (XXXVI). Thedebenzylation is carried out by per se known reaction, for example, themethod described in T. W. Green, Protective Groups in Organic Synthesis,3^(rd) Ed., 1999, Chapter of “Protection for the Amino Group”, etc. Theproduct can be used in the next reaction as a reaction solution as is ora crude product, or can be isolated from the reaction mixture accordingto a conventional method, and easily purified by conventional means ofseparation (e.g., recrystallization, distillation, chromatography,etc.).

Compound (IIg) is produced from Compound (IIf) by the same method asshown in Reaction Scheme 9 in which Compound (II) is produced fromCompound (IIa), if necessary.

In addition, Compound (VI) is also produced by a method described in thefollowing Reaction Scheme 12.

In Reaction Scheme 12, the group represented by —CO-Q is carbonic acidor a reactive derivative thereof, and other symbols have the samemeanings as defined above.

Compound (XXXVIII) is produced by reacting Compound (XXI) and Compound(XXXVII), if desired, under the presence of base.

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, etc., or the like.

Compound (XXXVII) is used in an amount of about 0.8 to about 5.0 moles,preferably about 1.0 to about 3.0 moles, relative to 1 mole of Compound(XXI).

The base is used in an amount of about 0.8 to about 5.0 moles,preferably about 1.0 to about 3.0 moles, relative to 1 mole of Compound(XXI). Further, if desired, quaternary ammonium salt may be added withthe base in producing Compound (XXXVIII). The “quaternary ammonium salt”is, for example, tetrabutylammonium iodide, etc.

The quaternary ammonium salt is used in an amount of about 0.1 to about2.0 moles, preferably about 0.5 to about 1.0 mole, relative to 1 mole ofCompound (XXI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 30 minutes to about 96 hours,preferably about 1 hour to about 72 hours. The reaction temperature isusually about 0 to about 120° C., preferably about 0 to about 60° C.

Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can be also used in steadof the above-mentioned reaction.

This reaction is carried out by reacting Compound (XXI) and Compound(XXXVII) in which L¹ is OH under the presence of azodicarboxylates(e.g., diethyl azodicarboxylate, etc.) and phosphines (e.g.,triphenylphosphine, tributylphosphine, etc.).

Compound (XXXVII) is used in an amount of about 0.8 to about 5.0 moles,preferably about 1.0 to about 3.0 moles, relative to 1 mole of Compound(XXI).

The “azodicarboxylates” and the “phosphines” are used respectively in anamount of about 0.8 to about 5.0 moles, preferably about 1.0 to about3.0 moles, relative to 1 mole of Compound (XXI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 5 minutes to about 48 hours,preferably about 30 minutes to about 24 hours. The reaction temperatureis usually about −20 to about 200° C., preferably about 0 to about 100°C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XXXIX) is produced by subjecting Compound (XXXVIII) to per seknown cyclization.

Q in the formula is preferably, a hydroxyl group, a halogen atom, etc.In this reaction, Compound (XXXVIII) is reacted with acid to giveCompound (XXXIX), if desired.

The “acid” is, for example, Lewis acids such as aluminum chloride, ironchloride, stannous chloride, tetrachloro titanium, boron trifluoridediethyl ether, etc., mineral acids such as polyphosphoric acid, sulfuricacid, etc., organic acids such as trifluoroacetic acid, methanesulfonicacid, p-toluenesulfonic acid, trifluoromethane sulfonic acid, etc.

The “acid” is used respectively in an amount of catalytic amount toexcessive amount relative to Compound (XXXVIII), preferably about 0.8 toabout 5 moles, relative to 1 mole of Compound (XXXVIII).

The present reaction is advantageously carried out without a solvent orwith a solvent inert to the reaction.

Such solvents are not particularly limited if the reaction proceeds, andinclude, for example, carbon disulfide, nitroalkanes such asnitromethane, etc., nitroaryls such as nitrobenzene, etc., halogenatedcarbons such as dichloromethane, 1,2-dichloroethane,1,2-dichlorobenzene, etc., organic acids such as acetic acid,trifluoroacetic acid, etc., acid anhydride such as acetic anhydride,trifluoroacetic anhydride, etc., or a mixed solvent thereof, or thelike.

The reaction time is usually about 10 minutes to about 96 hours,preferably about 10 minutes to about 12 hours. The reaction temperatureis usually about −70 to about 200° C., preferably about −40 to about150° C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XLIV) is produced from Compound (XXXIX) by the same method asthe method of producing Compound (IId) from Compound (XXV).

Compound (VI) is produced from Compound (XLIV) by the same method as themethod of producing Compound (I) from Compound (II).

Compound (IIf) and Compound (IIg) which are contained in Compound (II)are also produced by a method described in the following Reaction Scheme13 when R² of Compound (IIf) and Compound (IIg) is H.

In Reaction Scheme 13, Ar is an optionally substituted aromatic ring (abenzene ring, a naphthalene ring, a pyridine ring, a furan ring, athiophene ring, an imidazole ring, etc.), and other symbols have thesame meanings as defined above.

Compound (XLVI) is produced by reacting Compound (XLV) and ahalogenating reagent.

The “halogenating reagent” is, for example, chlorine, bromine, iodine,imides such as N-chlorosuccinimide or N-bromosuccinimide, etc., halogenadducts such as benzyltrimethylammonium tribromide, etc., or the like.The halogenating reagent is used in an amount of about 0.8 to about 5.0moles, preferably about 1.0 to about 2.0 moles, relative to 1 mole ofCompound (XLV).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., organic acids such asacetic acid, propionic acid, etc., nitroalkanes such as nitromethane,etc., aromatic amines such as pyridine, lutidine, quinoline, etc., or amixed solvent thereof, or the like.

The present reaction is carried out under the presence of base or Lewisacid or iron, if desired.

The “base” is, for example, basic salts such as sodium carbonate,calcium carbonate, cecium carbonate, sodium hydrogen carbonate, sodiumacetate, potassium acetate, etc., aromatic amines such as pyridine,lutidine, etc., tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc. The base is used in an amount of about 0.8 toabout 10 moles, relative to 1 mole of Compound (XLV).

The “Lewis acid” is, for example, iron chloride, aluminum chloride,boron trifluoride, etc. The Lewis acid is used in an amount of about0.01 to about 5 moles, relative to 1 mole of Compound (XLV).

The “iron” is used in an amount of about 0.01 to about 5 moles, relativeto 1 mole of Compound (XLV).

The reaction temperature is usually about −50 to about 150° C.,preferably about −20 to about 100° C. The reaction time is usually about5 minutes to about 24 hours, preferably about 10 minutes to about 12hours. The product can be used in the next reaction as a reactionsolution as is or a crude product, or can be isolated from the reactionmixture according to a conventional method, and easily purified byconventional means of separation (e.g., recrystallization, distillation,chromatography, etc.).

In addition, when a halogen atom is substituted on ring A of Compound(XLV), Compound (XLVI) can be produced without halogenation.

Compound (XLVII) can be produced by reacting Compound (XLVI) and atriflating agent under the presence of base.

The “triflating agent” is, for example, trifluoromethanesulfonic acid,trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride,N-phenylbis(trifluoromethanesulfonimide), etc.

The triflating agent is used in an amount of about 0.8 to about 5.0moles, preferably about 1.0 to about 3.0 moles, relative to 1 mole ofCompound (XLVI).

The “base” is, for example, aromatic amines such as pyridine, lutidine,etc., tertiary amines such as triethylamine, tripropylamine,tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine, etc., alkali metal hydrides such as sodium hydride,potassium hydride, etc., metal amides such as sodium amide, lithiumdiisopropylamide, lithium hexamethyldisilazide, etc., metal alkoxidessuch as sodium methoxide, sodium ethoxide, potassium tert-butoxide,etc., or the like.

The base is used in an amount of about 0.8 to about 5.0 moles,preferably about 1.0 to about 3.0 moles, relative to 1 mole of Compound(XLVI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 30 minutes to about 96 hours,preferably about 1 hour to about 72 hours. The reaction temperature isusually about 0 to about 120° C., preferably about 0 to about 60° C.

Compound (XLVIII) produced by subjecting Compound (XLVII) to Suzukicoupling.

This reaction is carried out by reacting Compound (XLVII) with boronicacids such as substituted boronic acid and substituted boronic acidester, etc. in a solvent under basic condition under the presence of atransitional metal catalyst.

The “boronic acids” are used in an amount of about 0.5 to about 10moles, preferably about 0.9 to about 3 moles, relative to 1 mole ofCompound (XLVII).

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc., metalalkoxides such as sodium methoxide, sodium ethoxide, sodiumtert-butoxide, potassium tert-butoxide, etc., or the like.

The “transitional metal catalyst” is, for example, a palladium catalystsuch as palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,1,1-bis(diphenylphosphino)ferrocene dichloropalladium,dichlorobis(triphenylphosphine)palladium, etc. The transitional metalcatalyst is used in an amount of about 0.001 to about 3 moles,preferably about 0.02 to about 0.2 moles, relative to 1 mole of Compound(XLVII).

The solvent is, for example, ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., alcoholssuch as methanol, ethanol, propanol, etc., hydrocarbons such as benzene,toluene, carbon disulfide, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., water or mixed solventthereof, or the like.

The reaction temperature is usually 0 to 250° C., preferably 50 to 150°C. The reaction time is usually about 5 minutes to about 48 hours,preferably about 30 minutes to about 24 hours.

In the present reaction, the reaction time can be shortened usingmicrowave reactor, etc.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (XLIX) is produced from Compound (XLVIII) by the same method asthe method of producing Compound (XXXVI) from Compound (XXXV) as shownin Reaction Scheme 11.

Compound (L) is produced from Compound (XLIX) by the same method as themethod of producing Compound (IIf) from Compound (XXXVI) as shown inReaction Scheme 11.

Compound (IIf) is produced from Compound (L) by the same method as themethod of producing Compound (XXXIV) from Compound (XXXIII).

Compound (IIg) is produced from Compound (IIf) by the same method as themethod of producing Compound (IId) from Compound (XXV).

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (LIV) can be also produced by a method described in thefollowing Reaction Scheme 14.

In Reaction Scheme 13, each symbol has the same meaning as definedabove.

Compound (LI) is produced by reacting Compound (XXI) and brominatingreagent.

The “brominating reagent” is, for example, bromine, N-bromosuccinimide,benzyltrimethylammonium tribromide, etc. bromine adducts, etc.

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc., alcohols such as methanol, ethanol, propanol, etc., hydrocarbonssuch as benzene, toluene, carbon disulfide, cyclohexane, hexane, etc.,amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.,halogenated hydrocarbons such as dichloromethane, chloroform,tetrachlorocarbon, 1,2-dichloroethane, etc., nitriles such asacetonitrile, propionitrile, etc., sulfoxides such as dimethylsulfoxide,etc., organic acids such as acetic acid, propionic acid, etc.,nitroalkanes such as nitromethane, etc., aromatic amines such aspyridine, lutidine, quinoline, etc., or a mixed solvent thereof, or thelike.

The reaction temperature is usually about 0 to about 150° C., preferablyabout 20 to about 100° C. The reaction time is usually about 5 minutesto about 24 hours, preferably about 10 minutes to about 12 hours.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (LIII) is produced by reacting Compound (LI) and Compound (LII)under the presence of base.

The “base” is, for example, basic salts such as sodium carbonate,potassium carbonate, cecium carbonate, sodium hydrogen carbonate, etc.,aromatic amines such as pyridine, lutidine, etc., tertiary amines suchas triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.,alkali metal hydrides such as sodium hydride, potassium hydride, etc.,metal amides such as sodium amide, lithium diisopropylamide, lithiumhexamethyldisilazide, etc., metal alkoxides such as sodium methoxide,sodium ethoxide, potassium tert-butoxide, etc., or the like.

Compound (LII) is used in an amount of about 0.7 moles to excessiveamount, relative to 1 mole of Compound (LI).

The base is used in an amount of about 0.8 to about 10 moles, preferablyabout 1.0 to about 5 moles, relative to 1 mole of Compound (LI).Further, if desired, quaternary ammonium salt may be added with thebase.

The “quaternary ammonium salt” is, for example, benzyltributylammoniumiodide, etc.

The quaternary ammonium salt is used in an amount of about 0.1 to about2.0 moles, preferably about 0.5 to about 1.0 mole, relative to 1 mole ofCompound (LI).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, ethers such as diethylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., hydrocarbonssuch as benzene, toluene, cyclohexane, hexane, etc., amides such asN,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenatedhydrocarbons such as dichloromethane, chloroform, tetrachlorocarbon,1,2-dichloroethane, etc., nitriles such as acetonitrile, propionitrile,etc., sulfoxides such as dimethylsulfoxide, etc., or a mixed solventthereof, or the like.

The reaction time is usually about 30 minutes to about 96 hours,preferably about 1 hour to about 72 hours. The reaction temperature isusually about 0 to about 120° C., preferably about 0 to about 60° C.

The product can be used in the next reaction as a reaction solution asis or a crude product, or can be isolated from the reaction mixtureaccording to a conventional method, and easily purified by conventionalmeans of separation (e.g., recrystallization, distillation,chromatography, etc.).

Compound (LIV) is produced by cyclization of Compound (LIII) under thepresence of a metallic compound (e.g., Grignard reagents, organiclithium reagents, magnesium, etc.).

The metallic compound is used in an amount of about 0.8 to about 30moles, preferably about 1.0 to about 10 moles, relative to 1 mole ofCompound (VIII).

The present reaction is advantageously carried out using a solvent inertto the reaction. Such solvents are not particularly limited if thereaction proceeds, and include, for example, hydrocarbons such ashexane, cyclohexane, benzene, toluene, xylene, etc., ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, etc., halogenated carbons such as dichloromethane,chloroform, tetrachlorocarbon, 1,2-dichloroethane, etc., or a mixedsolvent thereof, or the like.

The reaction time is usually about 10 minutes to about 24 hours,preferably about 30 minutes to about 5 hours. The reaction temperatureis usually about −100 to about 120° C., preferably about −80 to about60° C.

The product can be used in the next reaction as a crude product, or canbe isolated from the reaction mixture according to a conventionalmethod, and easily purified by conventional means of separation (e.g.,recrystallization, distillation, chromatography, etc.).

The compounds which are raw materials for the above-mentioned Compound(I), etc. may form a salt. Kinds of the salt are not particularlylimited if the reactions are achieved, and include, for example, thesalts that the above-mentioned Compound (I), etc. may form.

Configurational isomers ((E)- and (Z)-forms) of Compound (I), etc. andCompounds (Ia), (Ib), (Ic) and (Id) which are contained in Compound (I),and Compound (I′), can be isolated and purified by conventional means ofseparation (e.g., extraction, recrystallization, distillation,chromatography, etc.) to produce pure compounds at the point when theisomers are generated. Further, the corresponding pure isomers can bealso obtained by progressing isomerization of a double bond with an acidcatalyst, a transitional metal complex, a metal catalyst, a radicalspecies catalyst, an illumination or a strong base catalyst, or byheating, etc., according to the method described in New ExperimentalChemistry Lecture 14 (Japanese Society of Chemistry), pp. 251-253,Experimental Chemistry Lecture 19 (Japanese Society of Chemistry),4^(th) Ed., pp. 273-274 and analogous methods thereto.

In addition, stereoisomers of Compound (I), etc. are generated dependingon kinds of substituents, and these isomers which are isolated or mixed,are contained in the present invention.

Compound (I), etc. may be a hydrate or a non-hydrate.

In any case, Compound (I), etc. can be synthesized by deprotection,acylation, alkylation, hydrogenation, oxidation, reduction, carbon chainextension reaction, substituent exchange reaction, or a combination oftwo or more, if further desired.

When the objective compound is obtained in free form, it can beconverted to a salt by a conventional method. When the objectivecompound is obtained in salt form, it can be converted to free form oranother salt by a conventional method. Thus obtained Compound (I), etc.can be isolated and purified from the reaction solution by known meanssuch as solvent conversion, concentration, solvent extraction,fractional distillation, crystallization, recrystallization,chromatography, etc.

When compound (I) exists as configurational isomers, diastreomers,conformers, etc., the respective isomers can be isolated by theabove-mentioned means of isolation and purification. Further, whencompound (I), etc. are racemic compounds, they can be separated into (d)and (l) forms by any conventional optical resolution means.

In the above reactions, when the starting compounds have an amino group,a carboxyl group, a hydroxyl group, etc. as substituents, these groupsmay be protected by conventional protective groups such as thosegenerally employed in peptide chemistry, and the like. After thereaction, the protective groups may be removed to obtain the objectivecompound, if necessary.

The protective group is, for example, formyl or, C₁₋₆ alkyl-carbonyl(e.g., acetyl, propionyl, etc.), phenylcarbonyl, C₁₋₆ alkoxy-carbonyl(e.g., methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C₇₋₁₀aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), trityl, phthaloyl,etc, which are optionally substituted, respectively. The substituent is,for example, a halogen atom (e.g., fluorine, chlorine, bromine, iodine,etc.), C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.),nitro, etc. The number of the substituent is, for example, 1 to 3.

In addition, the protective group may be removed by per se known methodsor analogous methods thereto, for example, a method of treating theprotective group with an acid, a base, ultraviolet ray, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate, etc., or reduction.

Compound (I₀) and a prodrug thereof have modulating action oncannabinoid receptors of CB1 agonist, CB1 antagonist, or CB2 agonist,etc.

The primary compounds among the compounds represented by Formula (I₀)wherein the 2-position of the fused-heterocycle in Formula (I₀) is notsubstituted (e.g., the compound of Formula (I) wherein both of R¹ and R²are a hydrogen atom), have CB1 agonistic action, and useful for treatingand preventing various diseases as described in Clin. Pharmacokinet.,2003 42(4) 327-360. Specific examples include, but are not limited to,cerebrovascular disorders such as cerebral infarction, cerebralhemorrhage, etc.; head injury; spinal damage; atmospheric hypoxia andischemia by nerve gas damage; nausea, vomit by anticancer agent; lowappetite such as anorexia, cachexia, etc. in cancer and AIDS; nausea byemetics; seizure by multiple sclerosis; psychogenic pain; chronic pain;Tourette's syndrome, imbalance; motor function disorders such aslevodopa-induced motor disorders, etc.; asthma; glaucoma; allergy;inflammation; epilepsy; refractory hiccup; depression; bipolardepression; anxiety; dependency and withdrawal syndrome on opiate andalcohol; renal diseases such as renal failure, etc.; various syndromesof Alzheimer's dementia; autoimmune diseases such as multiple sclerosis,arthritis, rheumatism, Crohn's Disease, etc.; hypertension; cancer;diarrhea; respiratory tract obstruction; sleep apnea, etc.

The primary compounds among the compounds represented by Formula (I₀)wherein the 2-position of the fused-heterocycle in Formula (I₀) issubstituted (e.g., the compound of Formula (I) wherein both of R¹ and R²are not a hydrogen atom), have CB1 agonistic action, and are consideredto be useful for, but are not limited to, treating and preventinganxiety, mood disorders, delirium, general mental diseases,schizophrenia, depression, drug use-related diseases such as alcoholdependency, nicotine dependency, etc., neuropathy, migraine, mentalstress, epilepsy, motor disorders such as dyskinesia of Parkinson'sdisease, memory disorders, cognitive disorders, panic disorders,Parkinson's disease, Huntington chorea, Raynaud's Disease, tremor,obsessive-compulsive syndrome, geriatric or Alzheimer's disease,hyperkinesia, wake disorders, neuro-protection in neurodegenerativediseases, appetite suppression in intake disorders, excessive appetite,overeating and obesity, type II diabetes mellitus, digestive tractdisorders, diarrhea, ulcer, vomit, urinary tract or bladder functiondisorders, circulation disorders, infertility, inflammative pneumonia,infection, anticancer, smoking cessation, endotoxin shock, bleedingshock, hypotension and insomnia, and further, pain-relieving,potentiating opiate or non-opiate analgesics, and improving digestivetract movement. Pharmacological tools in human or animal can be used asitself or as labeled with radioisotope for detecting and labeling CB1receptor.

Further, the compounds represented by Formula (I₀) has broad CB2agonistic action, and are considered to be useful for, but are notlimited to, preventing or treating multiple sclerosis, neurodegenerativediseases, irritable bowel syndrome, Crohn's Disease, refluxoesophagitis, COPD, psoriasis, autoimmune diseases, graft rejection,allergic diseases, psychogenic pain, hepatitis virus or hypertension, orregulating immunity, etc.

The compound of the present invention has low toxicity (for example,acute toxicity, chronic toxicity, genotoxicity, reproduction toxicity,cardiotoxicity, drug interaction, carcinogenecity, etc.) and can beadministered safely alone or in the form of a pharmaceutical compositionprepared by formulating it with a pharmacologically acceptable carrieraccording to per se known means in such dosage forms as tablets(including sugar-coated tablets, film-coated tablets and orallydisintegrating tablets), powders, granules, capsules (including softcapsules), solutions, injections, suppositories, controlled releasedosage forms and patches, whether orally or by other routes (e.g.topically, rectally, intravenously, etc.).

The content of the compound of the present invention in the preparationof the present invention is about 0.001 to about 100% by weight based onthe total weight of the preparation.

The dosage is varied depending on the characteristics of the patient orthe recipient, the route of administration, the disease to be treated,and other factors. For example, when an injectable dosage form isadministered to an adult patient for the treatment of a brain trauma,the recommended dosage in terms of active ingredient of the presentcompound is about 0.001 to about 20 mg/kg body weight, preferably about0.005 to about 5 mg/kg body weight, and more preferably about 0.05 toabout 1 mg/kg body weight per day in a single dose or in divided doses.

The present compound can be used in combination with other activeingredients [(e.g., a thrombolytic agent (e.g., tissue plasminogenactivator, urokinase, etc.), an anticoagulant (e.g., argatroban,heparin, etc.), Factor X-inhibitor, thromboxane-synthetase inhibitor,(e.g., ozagrel, etc.), an antioxidant (e.g., edaravon, etc.), ananti-edema agent (e.g., glycerol, mannitol, etc.), neuron-creating orregenerating promoter (e.g., Akt/PKB activator, GSK-3β-inhibitor, etc.),acetylcholinesterase inhibitor (e.g., donepezil, rivastigmine,galantamine, zanapezil, etc.), a suppressor for production, secretion,accumulation, aggregation and/or deposition of β-amyloid protein[β-secretase inhibitor (e.g. the compound described in WO 98/38156, thecompound described in WO 02/2505, WO 02/2506 or WO 02/2512, OM99-2 (WO01/00663)), γ-secretase inhibitor, inhibitor of β-amyloid proteinaggregation (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368(JP-A-1999-514333), PPI-558 (JP-2001-500852), SKF-74652 (Biochem. J.(1999), 340(1), 283-289)), β-amyloid vaccine, β-amyloid decomposingenzyme, etc.], brain function enhancing agent (e.g., aniracetam,nicergoline, etc.), other treating agent for Parkinson's disease [(e.g.,dopamine receptor agonist (L-dopa, bromocriptine, pergolide, talipexol,pramipexol, cabergoline, adamantadine, etc.), monoamine oxidase (MAO)inhibitor (Deprenyl, selegiline, remacemide, riluzole, etc.),anticolinergics (e.g., trihexyphenidyl, biperiden, etc.), COMT inhibitor(e.g., entacapone, etc.)], an agent of treating amyotrophic lateralsclerosis (e.g., riluzole, etc., neuro-nutrition factor, etc.), an agentof treating hyperlipidemia such as a cholesterol-lowering agent, etc.[statins (e.g., flavastatin sodium, atrovastatin, simvastatin,rosuvastatin, etc.), fibrate (e.g., clofibrate, etc.),squalene-synthetase inhibitor], an agent of treating abnormal behavior,loitering, etc. which are involved in dementia (e.g., sedatives,anxiolytics, etc.), apotosis inhibitor (e.g., CPI-1189, IDN-6556,CEP-1347, etc.), an agent of promoting differentiating and regeneratingnerves (Leteprinim, Xaliproden (SR-57746-A), SB-216763, etc.],anti-hypertensives, an agent of treating diabetes mellitus,anti-depressive, anxiolytics, non-steroid anti-inflammative agent (e.g.,meloxicam, tenoxicam, indometacin, ibuprofen, celecoxib, rofecoxib,aspirin, etc.), disease-modifying anti-rheumatic drugs (DMARDs),anti-cytokine drugs (TNF inhibitor, MAP kinase inhibitor, etc.),steroids (e.g., dexamethasone, hexesterol, colchicines acetate, etc.),sexual hormones or derivatives thereof (e.g., progesterone, estradiol,estradiol benzoate, etc.), para-thyroid hormone (PTH), calcium receptorantagonist, interferon (e.g., interferon α, interferon β), etc.]. Theseother active ingredients can be formulated in combination with thepresent compound or salt thereof according to per se known methods toprovide a pharmaceutical composition (e.g., tablets, powders, granules,capsules (including soft capsules), solutions, injections,suppositories, controlled release dosage forms, etc.), or can beformulated separately to be administered to the same subject at the sametime or at time interval.

The pharmacologically acceptable carrier that can be used in themanufacture of a pharmaceutical composition of the present inventionincludes various kinds of organic or inorganic carriers which areconventionally used in pharmaceutical practice, such as excipient,lubricant, binder, and disintegrator for solid preparations; or thesolvent, solubilizer, suspending agent, isotonizing agent, buffer, andlocal anesthetic or soothing agent for liquid preparations. Further,common additives such as antiseptics, antioxidant, colorant, sweetener,adsorbent, wetting agent, etc. can also be incorporated, if necessary.

The excipient includes lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride, etc.

The lubricant includes magnesium stearate, calcium stearate, talc,colloidal silica, etc.

The binder includes, for example, crystalline cellulose, sucrose,D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, cane sugar,gelatin, methylcellulose, carboxymethylcellulose sodium, etc.

The disintegrator includes starch, carboxymethylcellulose,carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, L-hydroxypropylcellulose, etc. The solvent includes waterfor injection, alcohol, propylene glycol, macrogols, sesame oil, cornoil, olive oil, etc.

The solubilizer includes polyethylene glycol, propylene glycol,D-mannitol, benzyl benzoate, ethanol, trisaminomethane, hydrophilicsurfactant such as Tween 80(trademark), cholesterol, cyclodextrin (forexample, α-, β- or γ-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin, etc.) triethanolamine, sodium carbonate, sodiumcitrate, etc.

The suspending agent includes surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerylmonostearate, etc.; and hydrophilic macromolecular substances such aspolyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, etc.

The isotonizing agent includes glucose, D-sorbitol, sodium chloride,glycerin, D-mannitol, etc.

The buffer includes phosphate, acetate, carbonate, citrate, etc.

The local anesthetic includes benzyl alcohol, etc.

The antiseptic includes paraoxybenzoic acid esters, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.

The antioxidant includes sulfites, ascorbic acid, α-tocopherol, etc.

The following Reference Examples, Examples, Formulation Examples andExperimental examples are intended to describe the present invention infurther detail and should by no means be construed as defining the scopeof the invention.

As used in the following reference and working examples, the term “roomtemperature” generally means about 10 to 35° C. The symbol % stands forpercentage by weight unless otherwise indicated.

The other abbreviations used in the text have the following meanings.

s: singlet

d: doublet

dd: doublet of doublets

dt: doublet of triplets

t: triplet

q: quartet

septet: septet

m: multiplet

br: broad

J: coupling constant

Hz: Hertz

CDCl₃: deuterated chloroform

DMSO-d₆: deuterated dimethylsulfoxide

¹H-NMR: proton nuclear magnetic resonance

THF: tetrahydrofuran

DMF: dimethylformamide

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

For ¹H-NMR, proton on a hydroxyl group or an amino group has very gentlepeak, is not indicated. Further, data for a free form was described as afree base for a compound forming a salt.

Kiesselgel 60 made by Merk was used for silica gel chromatography, andChromatorex NH made by Fuji Silica Chemistry, Co., Ltd for basic silicagel chromatography.

REFERENCE EXAMPLE 1 Hydroxy(4-isopropylphenyl)acetic acid

To a mixture of lithium chloride (17.0 g, 418 mmol), potassium hydroxide(44.9 g, 800 mmol) and ice (150 g) was added a solution of bromoform(17.5 mL, 200 mmol) and 4-isopropyl benzaldehyde (30.3 mL, 200 mmol) in1,4-dioxane (150 mL) at 0° C., and the mixture was stirred at 5-10° C.for 24 hours and then stirred at 35° C. for 24 hours. The aqueous layerwas acidified with hydrochloric acid and was extracted with ethylacetate. The extract was washed with water and then was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain a residue, which was crystallized from hexane-ethylacetate to obtain 28.5 g (yield 73%) of the title compound. Meltingpoint: 156-157° C.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.0 Hz), 2.91 (1H, septet, J=7.0 Hz),5.21 (1H, s), 7.24 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 2Hunidentified.

REFERENCE EXAMPLE 23-(4-Isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one

To a mixture of hydroxy(4-isopropylphenyl)acetic acid synthesized inReference Example 1 (11.8 g, 60.8 mmol) and 2,3,5-trimethylphenol (12.4g, 91.2 mmol) was added 70% sulfuric acid (10 mL) at room temperature,and the mixture was stirred at 115° C. for 12 hours. The mixture wasadded to water and was extracted with diisopropyl ether. The extract waswashed with water and a saturated sodium hydrogen carbonate solution,and then was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain a residue, which waspurified by silica gel column chromatography (hexane ethyl acetate=8:1)to obtain 10.9 g (yield 65%) of the title compound. Melting point:107-108° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.6 Hz), 1.93 (3H, s), 2.24 (3H, s),2.29 (3H, s), 2.88 (1H, septet, J=6.6 Hz), 4.76 (1H, s), 6.76 (1H, s),7.07 (2H, d, J=8.1 Hz), 7.17 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 33-(4-Isopropylphenyl)-6,7-dimethyl-1-benzofuran-2(3H)-one

Using hydroxy(4-isopropylphenyl)acetic acid synthesized in ReferenceExample 1 and 2,3-dimethylphenol, the title compound was synthesized inthe same manner as in Reference Example 2. Yield 44%. Melting point:58-60° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.27 (3H, s), 2.32 (3H, s),2.88 (1H, septet, J=6.6 Hz), 4.85 (1H, s), 6.91 (1H, d, J=7.8 Hz), 6.95(1H, d, J=7.8 Hz), 7.13 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 43-(4-Isopropylphenyl)-4,6-dimethyl-1-benzofuran-2(3H)-one

Using hydroxy(4-isopropylphenyl)acetic acid synthesized in ReferenceExample 1 and 3,5-dimethylphenol, the title compound was synthesized inthe same manner as in Reference Example 2. Yield 45%. Melting point:76-77° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=7.0 Hz), 1.97 (3H, s), 2.38 (3H, s),2.88 (1H, septet, J=7.0 Hz), 4.73 (1H, s), 6.78 (1H, s), 6.84 (1H, s),7.07 (2H, d, J=8.2 Hz), 7.18 (2H, d, J=8.2 Hz).

REFERENCE EXAMPLE 5 5-Bromo-3-(4-isopropylphenyl)-1-benzofuran-2(3H)-one

Using hydroxy(4-isopropylphenyl)acetic acid synthesized in ReferenceExample 1 and 4-bromophenol, the title compound was synthesized in thesame manner as in Reference Example 2. Yield 30%. Melting point:157-158° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 2.90 (1H, septet, J=6.9 Hz),4.86 (1H, s), 7.06 (1H, d, J=8.7 Hz), 7.11 (2H, d, J=8.4 Hz), 7.23 (2H,d, J=8.4 Hz), 7.33 (1H, s), 7.47 (1H, d, J=8.7 Hz).

REFERENCE EXAMPLE 63-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-1-benzofuran-2(3H)-one

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one synthesizedin Reference Example 2 (2.10 g, 7.13 mmol) in DMF (30 mL) was addedsodium hydride (a 60% fluidized paraffin dispersion, 314 mg, 7.84 mmol)at 0° C., and the mixture was stirred at room temperature for 30minutes. To the reaction solution was added methyl iodide (1.11 g, 7.84mmol) and the mixture was stirred for at room temperature 30 minutes.Water was added to the reaction solution and the product was extractedwith ethyl acetate. The combined extract was washed with water, driedover magnesium sulfate and then concentrated under reduced pressure toobtain the residue, which was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain 2.07 g (yield 94%)of the title compound as an oily matter.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.94 (3H, s), 1.98 (3H, s),2.25 (3H, s), 2.29 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 6.77 (1H, s),7.09-7.22 (4H, m).

REFERENCE EXAMPLE 73-(4-Isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one

Using 3-(4-isopropylphenyl)-6,7-dimethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 3, the title compound was synthesizedin the same manner as in Reference Example 6. Yield 59%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.8 Hz), 1.87 (3H, s), 2.28 (3H, s),2.33 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 6.94 (1H, d, J=7.8 Hz), 6.94(1H, d, J=7.8 Hz), 7.17 (2H, d, J=8.4 Hz), 7.25 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 82-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-3,5,6-trimethylphenol

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one (8.42 g,28.6 mmol) obtained in Reference Example 2 in THF (80 mL) was addedlithium aluminum hydride (1.63 g, 42.9 mmol) at 0° C., and the mixturewas heated under reflux for 1 hour. Water was added to the reactionsolution and the product was extracted with ethyl acetate. The combinedextract was washed with water, dried over magnesium sulfate and thenconcentrated under reduced pressure. The obtained residue wascrystallized from hexane-ethyl acetate to obtain 8.00 g (yield 94%) ofthe title compound. Melting point: 101-102° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.13-2.35 (10H, m), 2.86 (1H,septet, J=6.9 Hz), 4.24 (1H, dd, J=10.8 Hz), 4.42 (1H, dd, J=10.8, 5.1Hz), 4.50 (1H, dd, J=5.1, 2.7 Hz), 6.58 (1H, s), 7.15 (4H, s), 8.01 (1H,br s).

REFERENCE EXAMPLE 96-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-2,3-dimethylphenol

Using 3-(4-isopropylphenyl)-6,7-dimethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 3, the title compound was synthesizedin the same manner as in Reference Example 8.

Yield 36%. Melting point: 83-84° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.2 Hz), 2.03 (1H, br s), 2.18 (3H, s),2.25 (3H, s), 2.87 (1H, septet, J=7.2 Hz), 4.18-4.39 (3H, m), 6.68 (1H,d, J=7.8 Hz), 6.77 (1H, d, J=7.8 Hz), 6.84 (1H, s), 7.14 (2H, d, J=9.0Hz), 7.18 (2H, d, J=9.0 Hz).

REFERENCE EXAMPLE 102-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-3,5-dimethylphenol

Using 3-(4-isopropylphenyl)-4,6-dimethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 4, the title compound was synthesizedin the same manner as in Reference Example 8. Yield 93%. Melting point:101-102° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 2.19 (3H, s), 2.25 (3H, s),2.27 (1H, br s), 2.86 (1H, septet, J=6.9 Hz), 4.21 (1H, dd, J=11.1, 2.7Hz), 4.39 (1H, dd, J=11.1, 5.1 Hz), 4.48 (1H, dd, J=5.1, 2.7 Hz), 6.57(1H, s), 6.62 (1H, s), 7.15 (4H, s), 8.14 (1H, br s).

REFERENCE EXAMPLE 114-Bromo-2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)phenol

Using 5-bromo-3-(4-isopropylphenyl)-1-benzofuran-2(3H)-one synthesizedin Reference Example 5, the title compound was synthesized in the samemanner as in Reference Example 8. Yield 44%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.38 (1H, br s), 2.88 (1H,septet, J=7.2 Hz), 4.18-4.37 (3H, m), 6.76 (1H, d, J=8.1 Hz), 7.08-7.25(6H, m), 7.47 (1H, br s).

REFERENCE EXAMPLE 122-(2-Hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-3,5,6-trimethylphenol

Using 3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 6, the title compound was synthesizedin the same manner as in Reference Example 8. Yield 83%. Melting point:116-117° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.73 (6H, s), 2.20 (3H, s),2.21 (3H, s), 2.56-2.64 (1H, m), 2.88 (1H, septet, J=6.9 Hz), 3.77 (1H,dd, J=11.1, 3.6 Hz), 4.13-4.22 (1H, m), 6.49 (1H, s), 7.11 (2H, d, J=8.4Hz), 7.15 (2H, d, J=8.4 Hz), 8.70 (1H, s).

REFERENCE EXAMPLE 133-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

To a solution of2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5,6-trimethylphenol obtainedin Reference Example 8 (7.85 g, 26.3 mmol) and triphenylphosphine (7.58g, 28.9 mmol) in THF (60 mL) was added diethyl azodicarboxylate (a 40%toluene solution, 12.6 g, 28.9 mmol) with ice-cooling, and the mixturewas stirred at room temperature for 1 hour. The solvent was concentratedunder reduced pressure to obtain the residue, which was purified bysilica gel column chromatography (hexane:ethyl acetate=10:1) to obtain5.70 g (yield 84%) of the title compound. Melting point: 48-49° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.15 (3H, s),2.23 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.37-4.56 (2H, m), 4.79-4.88(1H, m), 6.48 (1H, s), 7.06 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 143-(4-Isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran

Using 6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,3-dimethylphenolsynthesized in Reference Example 9, the title compound was synthesizedin the same manner as in Reference Example 13. Yield 80%. Melting point:50-51° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 2.18 (3H, s), 2.25 (3H, s),2.88 (1H, septet, J=6.9 Hz), 4.35-4.42 (1H, m), 4.62 (1H, t, J=8.7 Hz),4.82-4.90 (1H, m), 6.67 (1H, d, J=7.8 Hz), 6.75 (1H, d, J=7.8 Hz), 7.13(2H, d, J=9.0 Hz), 7.17 (2H, d, J=9.0 Hz).

REFERENCE EXAMPLE 153-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using 2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,5-dimethylphenolsynthesized in Reference Example 10, the title compound was synthesizedin the same manner as in Reference Example 13. Yield 85%. Melting point:46-47° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.0 Hz), 1.92 (3H, s), 2.29 (3H, s),2.86 (1H, septet, J=7.0 Hz), 4.35-4.53 (2H, m), 4.75-4.90 (1H, m), 6.47(1H, s), 6.55 (1H, s), 7.05 (2H, d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 165-Bromo-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran

Using 4-bromo-2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)phenol synthesizedin Reference Example 11, the title compound was synthesized in the samemanner as in Reference Example 13. Yield 62%. Melting point: 90-91° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.8 Hz), 2.90 (1H, septet, J=6.8 Hz),4.37-4.47 (1H, m), 4.56-4.67 (1H, m), 4.89 (1H, dd, J=9.6, 8.8 Hz), 6.74(1H, d, J=8.4 Hz), 7.07-7.29 (6H, m).

REFERENCE EXAMPLE 173-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran

Using2-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-3,5,6-trimethylphenolsynthesized in Reference Example 12, the title compound was synthesizedin the same manner as in Reference Example 13. Yield 95%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.74 (3H, s), 1.80 (3H, s),2.15 (3H, s), 2.22 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.38 (1H, d,J=8.4 Hz), 4.46 (1H, d, J=8.4 Hz), 6.45 (1H, s), 7.13 (2H, d, J=8.4 Hz),7.20 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 185-Bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

To a mixture of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 13 (6.10 g, 21.8 mmol) and sodiumacetate (1.97 g, 24.0 mmol) in acetonitrile (30 mL) was added bromine(1.17 mL, 22.9 mmol), and the mixture was stirred at the sametemperature for 1 hour. Water was poured into the reaction mixture,which was extracted with ethyl acetate. The extract was washed with asaturated sodium hydrogen carbonate solution and water, dried overmagnesium sulfate, filtered and then concentrated under reducedpressure. The obtained residue was crystallized from methanol to obtain7.90 g (yield 99%) of the title compound. Melting point: 86-87° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.04 (3H, s), 2.23 (3H, s),2.38 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.41 (1H, dd, J=8.4, 4.8 Hz),4.54 (1H, dd, J=9.0, 4.8 Hz), 4.81 (1H, t, J=9.0 Hz), 7.01 (2H, d, J=8.1Hz), 7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 195-Bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 14, the title compound was synthesizedin the same manner as in Reference Example 18. Yield 68%. Melting point:114-115° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.0 Hz), 2.23 (3H, s), 2.33 (3H, s),2.89 (1H, septet, J=7.0 Hz), 4.39 (1H, dd, J=8.4, 7.8 Hz), 4.54-4.66(1H, m), 4.86 (1H, dd, J=9.2, 8.4 Hz), 7.03 (1H, s), 7.11 (2H, d, J=8.4Hz), 7.18 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 205-Bromo-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 17, the title compound was synthesizedin the same manner as in Reference Example 18. Yield 98%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.74 (3H, s), 1.90 (3H, s),2.23 (3H, s), 2.38 (3H, s), 2.88 (1H, septet, J=6.9 Hz), 4.37 (1H, d,J=8.7 Hz), 4.42 (1H, d, J=8.7 Hz), 7.14 (2H, d, J=8.4 Hz), 7.19 (2H, d,J=8.4 Hz).

REFERENCE EXAMPLE 215-Bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-one

Using 3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 7, the title compound was synthesizedin the same manner as in Reference Example 18. Yield 73%. Melting point:116-117° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.86 (3H, s), 2.34 (3H, s),2.41 (3H, s), 2.88 (1H, septet, J=6.9 Hz), 7.15-7.25 (5H, m).

REFERENCE EXAMPLE 224-Bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphenol

Using5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 21, the title compound was synthesizedin the same manner as in Reference Example 8. Yield 83%. Melting point:110-111° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 1.58 (3H, s), 2.15 (3H, s),2.37 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 3.99 (1H, d, J=11.7 Hz), 4.23(1H, d, J=11.7 Hz), 6.27 (1H, br s), 7.19 (4H, s), 7.40 (1H, s), 1Hunidentified.

REFERENCE EXAMPLE 235-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

To a solution of3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran synthesizedin Reference Example 15 (5.62 g, 21.1 mmol) in acetonitrile (60 mL) wasadded N-bromosuccinimide (3.76 g, 21.1 mmol) at 0° C., and the mixturewas stirred at the same temperature for 1 hour.

The solvent was distilled off under reduced pressure to obtain aresidue, which was purified by silica gel column chromatography(hexane:ethyl acetate=10:1) to obtain 5.95 g (yield 82%) of the titlecompound. Melting point: 90-91° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.05 (3H, s), 2.39 (3H, s),2.86 (1H, septet, J=6.9 Hz), 4.41 (1H, dd, J=8.4, 4.5 Hz), 4.52 (1H, dd,J=9.0, 4.5 Hz), 4.78-4.86 (1H, m), 6.66 (1H, s), 7.01 (2H, d, J=8.1 Hz),7.13 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 24N-Benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

To a solution of5-bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 18 (920 mg, 2.56 mmol) and benzylamine(0.34 mL, 3.07 mmol) in toluene (10 mL), were added palladium acetate (6mg, 0.03 mmol) and BINAP (48 mg, 0.09 mmol) at room temperature, and themixture was stirred under argon stream for 15 minutes. Sodiumtert-butoxide (344 mg, 3.58 mmol) was added to the reaction solution atroom temperature, and then the mixture was heated under reflux for 18hours. Water was added to the reaction solution, which was extractedwith ethyl acetate, the organic layer was washed with water and asaturated brine and then was dried over anhydrous sodium sulfate, andthe solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=50:1) to obtain 900 mg (yield 91%) of the title compound as anoily matter. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.87 (3H, s), 2.20 (3H, s),2.27 (3H, s), 2.67-3.02 (2H, m), 3.91 (2H, s), 4.38 (1H, dd, J=8.4, 4.8Hz), 4.52 (1H, dd, J=9.0, 4.8 Hz), 4.80 (1H, t, J=9.0 Hz), 7.03 (2H, d,J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.20-7.42 (5H, m).

REFERENCE EXAMPLE 25N-Benzyl-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 19, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 85%. Melting point:108-109° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 2.08 (3H, s), 2.22 (3H, s),2.88 (1H, septet, J=7.0 Hz), 3.42 (1H, br s), 4.18 (2H, s), 4.28 (1H, t,J=7.5 Hz), 4.55-4.64 (1H, m), 4.79 (1H, t, J=9.0 Hz), 6.30 (1H, s), 7.11(2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 7.21-7.37 (5H, m).

REFERENCE EXAMPLE 26N-Benzyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 23, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 99%. Melting point:82-83° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s), 2.27 (3H, s),2.67-3.02 (2H, m), 3.93 (2H, s), 4.38 (1H, dd, J=8.4, 4.5 Hz), 4.49 (1H,dd, J=9.0, 4.5 Hz), 4.75-4.83 (1H, m), 6.59 (1H, s), 7.02 (2H, d, J=8.1Hz), 7.12 (2H, d, J=8.1 Hz), 7.19-7.39 (5H, m).

REFERENCE EXAMPLE 27N-Benzyl-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine

Using 5-bromo-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran synthesizedin Reference Example 16, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 89%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=6.9 Hz), 2.88 (1H, septet, J=6.9 Hz),3.42 (1H, br s), 4.20 (2H, s), 4.31 (1H, dd, J=8.7, 7.8 Hz), 4.51-4.59(1H, m), 4.80 (1H, dd, J=9.0, 8.7 Hz), 6.38 (1H, d, J=2.4 Hz), 6.46 (1H,dd, J=8.1, 2.4 Hz), 6.71 (1H, d, J=8.1 Hz), 7.08-7.37 (9H, m).

REFERENCE EXAMPLE 28N-Benzyl-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 20, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 25%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.73 (3H, s), 1.74 (3H, s),2.20 (3H, s), 2.27 (3H, s), 2.78-3.10 (2H, m), 3.88 (1H, d, J=13.2 Hz),3.93 (1H, d, J=13.2 Hz), 4.35

(1H, d, J=8.4 Hz), 4.39 (1H, d, J=8.4 Hz), 7.10-7.38 (9H, m).

REFERENCE EXAMPLE 29N-Benzyl-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

To a solution of4-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)-1-methylethyl)-2,3-dimethylphenolobtained in Reference Example 22 (830 mg, 2.21 mmol) andtriphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL) was added diethylazodicarboxylate (a 40% toluene solution, 1.06 g, 2.43 mmol) withice-cooling, and the mixture was stirred at room temperature for 1 hour.The solvent was concentrated under reduced pressure to obtain a residue,which was purified by silica gel column chromatography (hexane:ethylacetate=10:1) to obtain oily5-bromo-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran660 mg. To a solution of said compound (660 mg, 1.84 mmol) andbenzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) were added palladiumacetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at roomtemperature, and the mixture was stirred under argon stream for 15minutes.

Sodium tert-butoxide (248 mg, 2.58 mmol) was added to the reactionsolution at room temperature, and the mixture was heated under argonstream for 18 hours. Water was added to the reaction solution, which wasextracted with ethyl acetate, the organic layer was washed with waterand a saturated brine and then was dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=50:1), to obtain 660 mg (yield 77%) of the title compound as anoily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=7.0 Hz), 1.69 (3H, s), 2.09 (3H, s),2.22 (3H, s), 2.87 (1H, septet, J=7.0 Hz), 3.47 (1H, br s), 4.23 (2H,s), 4.35 (1H, d, J=8.4 Hz), 4.48 (1H, d, J=8.4 Hz), 6.32 (1H, s),7.07-7.42 (9H, m).

REFERENCE EXAMPLE 303-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

A mixture ofN-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 24 (900 mg, 2.33 mmol), 10%-palladiumcarbon (50% hydrous, 90 mg) and ammonium formate (294 mg, 4.66 mmol) inethanol (10 mL) was heated under reflux for 2 hours. The solid materialwas removed and the filtrate was concentrated under reduced pressure.Water and ethyl acetate were added to the residue to separate theorganic layer, and the aqueous layer was extracted with ethyl acetate.The combined organic layer was washed with water, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure to obtain a residue, which was crystallized from ethylacetate-hexane to obtain 510 mg (yield 74%) of the title compound.Melting point: 171-173° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.84 (3H, s), 2.11 (3H, s),2.20 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.26 (2H, br s), 4.30-4.41(1H, m), 4.47-4.60 (1H, m), 4.70-4.82 (1H, m), 7.05 (2H, d, J=8.1 Hz),7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 313-(4-Isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 25, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 88%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 2.00 (2H, br s), 2.08 (3H, s),2.20 (3H, s), 2.88 (1H, septet, J=6.9 Hz), 4.31 (1H, t, J=7.8 Hz), 4.56(1H, t, J=7.8 Hz), 4.75-4.83 (1H, m), 6.29 (1H, s), 7.14 (2H, d, J=9.0Hz), 7.17 (2H, d, J=9.0 Hz).

REFERENCE EXAMPLE 323-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 26, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 72%. Melting point:81-82° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.85 (3H, s), 2.18 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.07 (2H, br s), 4.35 (1H, dd, J=8.4, 4.5Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz), 4.71-4.80 (1H, m), 6.54 (1H, s), 7.03(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 333-(4-Isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine

Using N-benzyl-3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 27, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 77%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 2.88 (1H, septet, J=6.9 Hz),3.32 (2H, br s), 4.32 (1H, dd, J=8.7, 7.5 Hz), 4.49-4.57 (1H, m), 4.80(1H, dd, J=9.0, 8.7 Hz), 6.38 (1H, d, J=2.4 Hz), 6.49 (1H, dd, J=8.1,2.4 Hz), 6.67 (1H, d, J=8.1 Hz), 7.12 (2H, d, J=8.4 Hz), 7.16 (2H, d,J=8.4 Hz).

REFERENCE EXAMPLE 343-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 28, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 79%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.69 (3H, s), 1.77 (3H, s),2.15 (3H, s), 2.20 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.10 (2H, brs), 4.30 (1H, d, J=8.4 Hz), 4.34 (1H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4Hz), 7.22 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 353-(4-Isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 29, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 71%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.69 (3H, s), 2.09 (3H, s),2.20 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 3.30 (2H, br s), 4.35 (1H, d,J=8.7 Hz), 4.50 (1H, d, J=8.7 Hz), 6.29 (1H, s), 7.14 (2H, d, J=8.1 Hz),7.23 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 36 2-(2,3-Dimethylphenoxy)-2-methylpropionic acid

To a solution of 2,3-dimethylphenol (25.0 g, 205 mmol) indimethylsulfoxide (200 mL) were added ethyl 2-bromo-isobutyrate (60 mL,409 mmol) and potassium carbonate (56.5 g, 409 mmol) at roomtemperature, and the mixture was stirred for 36 hours. Water was addedto the reaction solution and the mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated brine,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure to obtain crude oily ethyl2-(2,3-dimethylphenoxy)-2-methylpropionate. 12 N Aqueous sodiumhydroxide solution (20 mL, 240 mmol) was added to the mixed solution ofthis compound in THF (160 mL) and methanol (40 mL) at room temperature,stirred for 12 hours, and then concentrated under reduced pressure.Water and hydrochloric acid were added to the reaction solution toacidity the aqueous layer, which was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated brine and then wasdried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain a residue, which was crystallized from ethylacetate-hexane to obtain 21.3 g (yield 50%) of the title compound.Melting point: 71-73° C.

¹H-NMR (CDCl₃) δ: 1.60 (6H, s), 2.16 (3H, s), 2.27 (3H, s), 6.72 (1H, d,J=7.8 Hz), 6.88 (1H, d, J=7.5 Hz), 7.00 (1H, 7, J=7.8 Hz), 1Hunidentified.

REFERENCE EXAMPLE 37 2-(3,5-Dimethylphenoxy)-2-methylpropionic acid

Using 3,5-dimethylphenol, the title compound was synthesized in the samemanner as in Reference Example 36.

Yield 96%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.59 (6H, s), 2.27 (6H, s), 6.56 (1H, s), 6.72 (1H,s).

REFERENCE EXAMPLE 38 2-(2,5-Dimethylphenoxy)-2-methylpropionic acid

Using 2,5-dimethylphenol, the title compound was synthesized in the samemanner as in Reference Example 36.

Yield 57%. Melting point: 107-109° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.62 (6H, s), 2.20 (3H, s), 2.27 (3H, s), 6.64 (1H,s), 6.77 (1H, d, J=7.5 Hz), 7.05 (1H, d, J=7.5 Hz), 9.50 (1H, br s).

REFERENCE EXAMPLE 39 2-(2,3,5-Trimethyl phenoxy)-2-methylpropionic acid

Using 2,3,5-trimethylphenol, the title compound was synthesized in thesame manner as in Reference Example 36.

Yield 65%. Melting point: 91-94° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.59 (6H, s), 2.12 (3H, s), 2.22 (3H, s), 2.23 (3H,s), 6.53 (1H, s), 6.71 (1H, s), 1H unidentified.

REFERENCE EXAMPLE 40 2-(3,4,5-Trimethyl phenoxy)-2-methylpropionic acid

Using 3,4,5-trimethylphenol, the title compound was synthesized in thesame manner as in Reference Example 36.

Yield 57%. Melting point: 77-78° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.56 (6H, s), 2.11 (3H, s), 2.24 (6H, s), 6.61 (2H,s), 1H unidentified.

REFERENCE EXAMPLE 41 2,2,6,7-Tetramethyl-1-benzofuran-3(2H)-one

To a solution of 2-(2,3-dimethylphenoxy)-2-methylpropionic acid obtainedin Reference Example 36 (21.0 g, 101 mmol) in THF (200 mL) was added DMF(0.1 mL), and then to the mixture was added dropwise oxalyl chloride(10.6 mL, 121 mmol). The reaction solution was warmed to roomtemperature, stirred for 1 hour, and then concentrated under reducedpressure. The residue was dissolved in dichloromethane (200 mL), towhich was added aluminum chloride (32.3 g, 242 mmol) at −70° C. orlower, and then warmed to room temperature over 12 hours. The reactionsolution was added to water with ice-cooling and dichloromethane wasdistilled off under reduced pressure, which was extracted with ethylacetate. The organic layer was washed with water, a saturated sodiumhydrogen carbonate solution, water and a saturated brine, and then wasdried over anhydrous sodium sulfate. The residue after distilling offthe solvent under reduced pressure was crystallized from hexane toobtain 17.5 g (yield 71%) of the title compound. Melting point: 79-81°C. (methanol).

¹H-NMR (CDCl₃) δ: 1.46 (6H, s), 2.21 (3H, s), 2.35 (3H, s), 6.88 (1H, d,J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz).

REFERENCE EXAMPLE 42 2,2,4,6-Tetramethyl-1-benzofuran-3(2H)-one

Using 2-(3,5-dimethylphenoxy)-2-methylpropionic acid obtained inReference Example 37, the title compound was synthesized in the samemanner as in Reference Example 41.

Yield 92%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 2.37 (3H, s), 2.54 (3H, s), 6.62 (1H,s), 6.66 (1H, s).

REFERENCE EXAMPLE 43 2,2,4,7-Tetramethyl-1-benzofuran-3(2H)-one

Using 2-(2,5-dimethylphenoxy)-2-methylpropionic acid obtained inReference Example 38, the title compound was synthesized in the samemanner as in Reference Example 41.

Yield 97%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.45 (6H, s), 2.25 (3H, s), 2.55 (3H, s), 6.70 (1H, d,J=7.5 Hz), 7.26 (1H, d, J=7.5 Hz).

REFERENCE EXAMPLE 442,2,4,6,7-Pentamethyl-2,3-dihydro-1-benzofuran-3(2H)-one

Using 2-(2,3,5-trimethyl phenoxy)-2-methylpropionic acid obtained inReference Example 39, the title compound was synthesized in the samemanner as in Reference Example 41. Yield 33%. Melting point: 99-101° C.(hexane).

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 2.16 (3H, s), 2.30 (3H, s), 2.52 (3H,s), 6.63 (1H, s).

REFERENCE EXAMPLE 45 2,2,4,5,6-Pentamethyl-1-benzofuran-3(2H)-one

Using 2-(3,4,5-trimethyl phenoxy)-2-methylpropionic acid obtained inReference Example 40, the title compound was synthesized in the samemanner as in Reference Example 41. Yield 90%. Melting point: 77-78° C.(hexane).

¹H-NMR (CDCl₃) δ: 1.42 (6H, s), 2.14 (3H, s), 2.34 (3H, s), 2.57 (3H,s), 6.73 (1H, s).

REFERENCE EXAMPLE 46 2,2,6,7-Tetramethyl-5-nitro-1-benzofuran-3(2H)-one

To a solution of 2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one obtained inReference Example 41 (5.20 g, 27.3 mmol) in anhydrous trifluoroaceticacid (50 mL) and chloroform (5 mL) was added ammonium nitrate (2.10 g,32.8 mmol) at 0° C., and the mixture was stirred at the same temperaturefor 2 hours, and then concentrated under reduced pressure. Water wasadded to the residue, which was extracted with ethyl acetate. Theextract was washed with water and a saturated sodium hydrogen carbonatesolution, and then was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to obtain aresidue, which was purified by silica gel column chromatography(hexane:ethyl acetate=50:1) to obtain 5.40 g (yield 84%) of the titlecompound. Melting point: 131-132° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.50 (6H, s), 2.32 (3H, s), 2.52 (3H, s), 8.08 (1H,s).

REFERENCE EXAMPLE 47 2,2,4,7-Tetramethyl-5-nitro-1-benzofuran-3(2H)-one

Using 2,2,4,7-tetramethyl-1-benzofuran-3(2H)-one obtained in ReferenceExample 43, the title compound was synthesized in the same manner as inReference Example 46.

Yield 46%. Melting point: 124-126° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.50 (6H, s), 2.32 (3H, s), 2.87 (3H, s), 8.11 (1H,s).

REFERENCE EXAMPLE 48 5-Bromo-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one

Using 2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained in ReferenceExample 42, the title compound was synthesized in the same manner as inReference Example 18.

Yield 73%. Melting point: 63-64° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 2.48 (3H, s), 2.68 (3H, s), 6.83 (1H,s).

REFERENCE EXAMPLE 495-Bromo-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one

Using 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3(2H)-one obtainedin Reference Example 44, the title compound was synthesized in the samemanner as in Reference Example 18. Yield 73%. Melting point: 92-93° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 2.26 (3H, s), 2.47 (3H, s), 2.66 (3H,s).

REFERENCE EXAMPLE 507-Bromo-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one

Using 2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one obtained in ReferenceExample 45, the title compound was synthesized in the same manner as inReference Example 18.

Yield 79%. Melting point: 145-146° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.49 (6H, s), 2.23 (3H, s), 2.49 (3H, s), 2.55 (3H,s).

REFERENCE EXAMPLE 515-(Benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one

Using 5-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3(2H)-oneobtained in Reference Example 48, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 75%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 2.35 (3H, s), 2.54 (3H, s), 3.02 (1H, brs), 3.99 (2H, s), 6.73 (1H, s), 7.24-7.42 (5H, m).

REFERENCE EXAMPLE 525-(Benzylamino)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one

Using 5-bromo-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 49, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 88%. Melting point: 98-99° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 2.21 (3H, s), 2.35 (3H, s), 2.50 (3H,s), 3.04 (1H, br s), 3.94 (2H, s), 7.26-7.41 (5H, m).

REFERENCE EXAMPLE 537-(Benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one

Using 7-bromo-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 50, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 72%. Melting point: 108-109° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.38 (6H, s), 2.14 (3H, s), 2.28 (3H, s), 2.51 (3H,s), 3.61 (1H, br s), 4.27 (2H, s), 7.19-7.37 (5H, m).

REFERENCE EXAMPLE 54 5-Amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one

A mixture of 2,2,6,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one obtainedin Reference Example 46 (5.0 g, 21.3 mmol), 10%-palladium carbon (50%hydrous, 500 mg) and ammonium formate (7.06 g, 85.0 mmol) in methanol(100 mL) was heated under reflux for two hours. The solid material wasremoved and the filtrate was concentrated under reduced pressure. Waterand ethyl acetate were added to the residue to separate the organiclayer, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with water, dried over anhydroussodium sulfate and then concentrated under reduced pressure. The solventwas distilled off under reduced pressure to obtain a residue, which wascrystallized with ethyl acetate-hexane to obtain 4.0 g (yield 92%) ofthe title compound. Melting point: 149-150° C.

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 2.19 (3H, s), 2.24 (3H, s), 3.50 (2H, brs), 6.78 (1H, s).

REFERENCE EXAMPLE 55 5-Amino-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one

Using 5-(benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 51, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 95%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 2.19 (3H, s), 2.24 (3H, s), 3.50 (2H, brs), 6.78 (1H, s).

REFERENCE EXAMPLE 56 5-Amino-2,2,4,7-tetramethyl-1-benzofuran-3(2H)-one

Using 2,2,4,7-tetramethyl-5-nitro-1-benzofuran-3(2H)-one obtained inReference Example 47, the title compound was synthesized in the samemanner as in Reference Example 54. Yield 97%. Melting point: 124-126° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.42 (6H, s), 2.21 (3H, s), 2.40 (3H, s), 3.40 (2H, brs), 6.82 (1H, s).

REFERENCE EXAMPLE 575-Amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one

Using 5-(benzylamino)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 52, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 88%. Melting point:92-93° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.41 (6H, s), 2.19 (3H, s), 2.21 (3H, s), 2.45 (3H,s), 3.44 (2H, br s).

REFERENCE EXAMPLE 587-Amino-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one

Using 7-(benzylamino)-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 53, the title compound was synthesized inthe same manner as in Reference Example 30. Yield: quantitative. Meltingpoint: 141-142° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 2.16 (3H, s), 2.19 (3H, s), 2.50 (3H,s), 3.59 (2H, br s).

REFERENCE EXAMPLE 59 tert-Butyl(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate

A solution of 5-amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 54 (3.89 g, 19.5 mmol) and dicarbonic acidditert-butyl (6.73 mL, 29.3 mmol) in THF (50 mL) was heated under refluxfor 16 hours. Water was added to the residue to separate the organiclayer, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layer was washed with water, dried over anhydroussodium sulfate and then concentrated under reduced pressure. Theobtained residue was crystallized with hexane-ethyl acetate to obtain4.80 g (yield 81%) of the title compound. Melting point: 154-155° C.

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 1.50 (9H, s), 2.24 (3H, s), 2.25 (3H,s), 6.12 (1H, br s), 7.58 (1H, s).

REFERENCE EXAMPLE 60 tert-Butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using 5-amino-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained inReference Example 55, the title compound was synthesized in the samemanner as in Reference Example 59. Yield 71%. Melting point: 156-157° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 1.50 (9H, s), 2.24 (3H, s), 2.25 (3H,s), 6.12 (1H, br s), 7.58 (1H, s).

REFERENCE EXAMPLE 61 tert-Butyl(2,2,4,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using 5-amino-2,2,4,7-tetramethyl-1-benzofuran-3(2H)-one obtained inReference Example 56, the title compound was synthesized in the samemanner as in Reference Example 59. Yield 96%. Melting point: 144-145° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 1.51 (9H, s), 2.25 (3H, s), 2.47 (3H,s), 6.11 (1H, br s), 7.66 (1H, s).

REFERENCE EXAMPLE 62 tert-Butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 57, the title compound was synthesized in the samemanner as in Reference Example 59. Yield 90%. Melting point: 105-106° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.42 (6H, s), 1.51 (9H, s), 2.19 (3H, s), 2.25 (3H,s), 2.49 (3H, s), 5.81 (1H, br s).

REFERENCE EXAMPLE 633,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a solution of 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 57 (3.00 g, 13.7 mmol) andtert-butylacetyl chloride (2.03 g, 15.1 mmol) in dichloromethane (30 mL)was added triethylamine (2.3 mL, 16.4 mmol) at room temperature, and themixture was stirred at room temperature for 30 minutes. Water was addedto the residue to separate the organic layer, and the aqueous layer wasextracted with dichloromethane. The combined organic layer was washedwith 1 N hydrochloric acid and a saturated sodium hydrogen carbonatesolution, dried over magnesium sulfate, filtered, and then concentratedunder reduced pressure. The residue was crystallized from ethylacetate-hexane to obtain the targeted product 2.34 g (yield 54%).Melting point: 155-156° C.

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.43 (6H, s), 2.19 (3H, s), 2.22 (3H,s), 2.32 (2H, s), 2.47 (3H, s), 6.62 (1H, br s).

REFERENCE EXAMPLE 643,3-Dimethyl-N-(2,2,4,5,6-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-7-yl)butanamide

Using 7-amino-2,2,4,5,6-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 58, the title compound was synthesized in the samemanner as in Reference Example 63. Yield 76%. Melting point: 158-159° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.40 (6H, s), 2.16 (3H, s), 2.24 (3H,s), 2.32 (2H, s), 2.54 (3H, s), 6.78 (1H, br s).

REFERENCE EXAMPLE 653,3-Dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using 5-amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one obtained inReference Example 54, the title compound was synthesized in the samemanner as in Reference Example 63. Yield 88%. Melting point: 175-176° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.44 (6H, s), 2.24-2.26 (8H, m), 6.84(1H, br s), 7.50 (1H, s).

REFERENCE EXAMPLE 66 tert-Butyl(7-bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-1-benzofura-5-yl)carbamate

To a solution oftert-butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 60 (4.86 g, 15.9 mmol) in acetonitrile (70mL) was added N-bromosuccinimide (5.67 g, 31.8 mmol) was heated underreflux for 1.5 hours. The reaction solution was cooled to roomtemperature, followed by addition of water, which was extracted withethyl acetate, and the organic layer was washed with water and asaturation brine, dried over anhydrous sodium sulfate, and then wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate:hexane=3:7), and then wasrecrystallized with ethyl acetate-hexane to obtain 4.40 g (yield 72%) ofthe title compound. Melting point: 131-132° C.

¹H-NMR (CDCl₃) δ: 1.33-1.55 (15H, m), 2.46 (3H, s), 2.49 (3H, s), 5.87(1H, br s).

REFERENCE EXAMPLE 67 3-Bromo-2,4,5-trimethylbenzaldehyde

To a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144 mmol) indichloromethane (200 mL) was added aluminum chloride (48.0 g, 360 mmol)with ice-cooling, and the mixture was warmed to room temperature.Bromine (7.80 mL, 151 mmol) was added dropwised to the reaction solutionat room temperature, the mixture was stirred for 4 hours, water wasadded to the reaction solution, and dichloromethane was distilled offunder reduced pressure.

The residue was extracted with ethyl acetate and the organic layer waswashed with water, a saturated sodium hydrogen carbonate solution, 5%sodium sulfite aqueous solution, water and a saturated brine. Theorganic layer was dried over anhydrous sodium sulfate and then wasconcentrated under reduced pressure to obtain 32.5 g (yield 100%) of thetitle compound. Melting point: 108-110° C.

¹H-NMR (CDCl₃) δ: 2.38 (3H, s), 2.46 (3H, s), 2.73 (3H, s), 7.54 (1H,s), 10.21 (1H, s).

REFERENCE EXAMPLE 68 3-Bromo-2,4,5-trimethylphenol

To a solution of 3-bromo-2,4,5-trimethylbenzaldehyde obtained inReference Example 67 (32.0 g, 141 mmol) in THF (100 mL) was addedmethanol (200 mL) with ice-cooling, followed by addition ofp-toluenesulfonic acid monohydrate (5.40 g, 28.4 mmol) with ice-cooling.Hydrogen peroxide

(30%, 24.0 g, 212 mmol) was added dropwise to the reaction solution at10° C. or lower, and the mixture was warmed to room temperature andstirred for 12 hours. Then the reaction solution was stirred at 50° C.for 36 hours, followed by addition of an aqueous sodium sulfitesolution, and methanol and THF were distilled off under reducedpressure. The residue was extracted with ethyl acetate, the organiclayer was washed with water and a saturated brine, and then was driedover anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to obtain aresidue, which was purified by silica gel column chromatography(hexane:ethyl acetate=10:1) to obtain 9.1 g (yield 30%) of the titlecompound. Melting point: 86-88° C.

¹H-NMR (CDCl₃) δ: 2.25 (3H, s), 2.30 (3H, s), 2.32 (3H, s), 4.63 (1H,s), 6.56 (1H, s).

REFERENCE EXAMPLE 692-(3-Bromo-2,4,5-trimethylphenoxy)-2-methylpropionic acid

Using 3-bromo-2,4,5-trimethylphenol obtained in Reference Example 68,the title compound was synthesized in the same manner as in ReferenceExample 36. Yield 40%. Melting point: 151-153° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.59 (6H, s), 2.26 (3H, s), 2.33 (6H, s), 6.67 (1H,s), 9.60 (1H, br s).

REFERENCE EXAMPLE 706-Bromo-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one

Using 2-(3-bromo-2,4,5-trimethylphenoxy)-2-methylpropionic acid obtainedin Reference Example 69, the title compound was synthesized in the samemanner as in Reference Example 41. Yield 97%. Melting point: 125-127° C.

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 2.34 (3H, s), 2.37 (3H, s), 2.60 (3H,s).

REFERENCE EXAMPLE 716-(Benzylamino)-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one

Using 6-bromo-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 70, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 95%. Melting point: 79-83° C.

¹H-NMR (CDCl₃) δ: 1.43 (6H, s), 2.11 (3H, s), 2.16 (3H, s), 2.55 (3H,s), 3.86 (1H, br s), 4.34 (2H, s), 7.26-7.42 (5H, m).

REFERENCE EXAMPLE 726-Amino-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one

Using 6-(benzylamino)-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 71, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 87%. Melting point:150-151° C.

¹H-NMR (CDCl₃) δ: 1.41 (6H, s), 2.04 (3H, s), 2.06 (3H, s), 2.55 (3H,s), 4.27 (2H, br s).

REFERENCE EXAMPLE 73(2,2,4,5,7-Pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamide

A mixture of formic acid (5 mL) with6-amino-2,2,4,5,7-pentamethyl-1-benzofuran-3(2H)-one (700 mg, 3.19 mmol)obtained in Reference Example 72, was heated under reflux for 5 hours.The solvent was distilled off under reduced pressure, water and ethylacetate were added to the residue, and the aqueous layer was extractedwith ethyl acetate. The combined organic layer was washed with water anda saturated sodium hydrogen carbonate solution, dried over anhydroussodium sulfate, and then concentrated under reduced pressure. Theobtained residue was crystallized from hexane-ethyl acetate to obtain640 mg (yield 81%) of the title compound. Melting point: 191-192° C.

¹H-NMR (CDCl₃) δ: 1.40-1.52 (6H, m), 2.00-2.28 (3H, m), 2.56, 2.57 (1.5Hx2, s), 2.60 (3H, s), 7.07 (0.5H, br s), 7.20-7.35 (0.5H, m), 8.18(0.5H, d, J=11.6 Hz), 8.46 (0.5H, d, J=1.4 Hz).

REFERENCE EXAMPLE 743-(4-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride

To a solution of 4-bromocumene (6.25 g, 31.4 mmol) in THF (50 mL) wasadded dropwise a solution of n-butyllithium in hexane (1.60 M, 19.6 mL,31.4 mmol) under arogon atmosphere at −78° C., and the mixture wasstirred at the same temperature for 30 minutes. Then, to the reactionsolution was added dropwise a solution of tert-butyl(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 59 (500 mg, 2.02 mmol) in THF (5 mL) atthe same temperature, and the reaction solution was stirred at roomtemperature for 1 hour, followed by addition of water, which wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=10:1) to obtain oilytert-butyl(3-hydroxy-3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate.A mixture of said compound with trifluoroacetic acid (10 mL) was addedtriethylsilane (1.0 mL, 6.4 mmol) with ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure, and to the residue was added asaturated sodium hydrogen carbonate solution to alkalify the aqueouslayer, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=10:1)to obtain the free salt of the title compound. Then, it was madehydrochloride in a 4 N hydrochloric acid/methanol solution to obtain2.03 g (yield 37%) of the title compound. Melting point: 166-168° C.(decomp.) (methanol).

¹H-NMR (DMSO-d₆) δ: 0.90 (3H, s), 1.19 (6H, d, J=6.8 Hz), 1.51 (3H, s),2.14 (3H, s), 2.21 (3H, s), 2.87 (1H, septet, J=6.8 Hz), 4.39 (1H, s),6.96 (1H, s), 6.97 (2H, d, J=8.0 Hz), 7.20 (2H, d, J=8.0 Hz), 10.1 (2H,br s), 1H unidentified.

REFERENCE EXAMPLE 753-(4-Isopropylphenyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride

Using tert-butyl(2,2,4,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 61 and 4-bromocumene, the title compoundwas synthesized in the same manner as in Reference Example 74.

Yield 78%. Melting point: 239-240° C. (decomp.) (methanol).

¹H-NMR (DMSO-d₆) δ: 0.97 (3H, s), 1.17 (6H, d, J=6.9 Hz), 1.44 (3H, s),1.85 (3H, s), 2.15 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 4.29 (1H, s),6.58-7.27 (5H, m), 9.98 (2H, br s), 1H unidentified.

REFERENCE EXAMPLE 763-(4-Tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride

Using tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 62 and 4-bromo-tert-butylbenzene, thetitle compound was synthesized in the same manner as in ReferenceExample 74. Yield 23%. Melting point: 265-267° C. (decomp.) (methanol).

¹H-NMR (DMSO-d₆) δ: 0.96 (3H, s), 1.25 (9H, s), 1.43 (3H, s), 1.90 (3H,s), 2.12 (3H, s), 2.24 (3H, s), 4.26 (1H, s), 6.60-7.40 (4H, m), 9.46(2H, br s), 1H unidentified.

REFERENCE EXAMPLE 773-(4-Isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine

To a solution of 4-bromocumene (2.01 g, 10.1 mmol) in THF (20 mL) wasadded dropwise a solution of n-butyllithium in hexane (1.60 M, 6.25 mL,10.0 mmol) under arogon atmosphere at −78° C., and the mixture wasstirred at the same temperature for 30 minutes. Then, to the reactionsolution was added dropwise a solution of(2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamideobtained in Reference Example 73 (500 mg, 2.02 mmol) in THF (5 mL) atthe same temperature, and the reaction solution was stirred at roomtemperature for 1 hour, followed by addition of water, which wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) to obtain3-hydroxy-3-(4-isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)formamide.To a mixture of said compound with trifluoroacetic acid (5 mL) was addedtriethylsilane (0.5 mL, 3.2 mmol) with ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure, and to the residue was added asaturated sodium hydrogen carbonate solution to alkalify the aqueouslayer, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure.

To a solution of the obtained residue in methanol (20 mL) was addedconcentrated hydrochloric acid, and the mixture was heated under refluxfor 2 hours. The solvent was distilled off under reduced pressure andthe residue was neutralized with a 12 N aqueous sodium hydroxidesolution. After extracting with ethyl acetate, the organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to obtain 440 mg (yield 67%) of the title compound. Meltingpoint: 120-121° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.21 (6H, d, J=7.0 Hz), 1.48 (3H, s),1.84 (3H, s), 2.01 (3H, s), 2.10 (3H, s), 2.85 (1H, septet, J=6.9 Hz),3.58 (2H, br s), 4.07 (1H, s), 6.60-7.12 (4H, m).

REFERENCE EXAMPLE 783-(4-Isopropylphenyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine

Using tert-butyl(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 60 and 4-bromocumene, the title compoundwas synthesized in the same manner as in Reference Example 74.

Yield 89%. Melting point: 98-100° C. (methanol).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.21 (6H, d, J=7.2 Hz), 1.48 (3H, s),1.79 (3H, s), 2.18 (3H, s), 2.85 (1H, septet, J=7.2 Hz), 4.06 (1H, s),4.60 (2H, br s), 6.49 (1H, s), 6.60-7.10 (4H, m).

REFERENCE EXAMPLE 793-Benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine

A solution of(2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl)formamideobtained in Reference Example 73 (600 mg, 2.43 mmol) in THF (5 mL) wasadded dropwise to a solution of benzylmagnesium chloride (a 2.0 M THFsolution, 10.0 mL, 20.0 mmol) in THF (20 mL) under argon atmosphere, andthe mixture was stirred at room temperature for 2 hours. Water was addedthereto, which was extracted with ethyl acetate. The organic layer waswashed with 1 N hydrochloric acid, dried over anhydrous sodium sulfate,and then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain(3-benzyl-3-hydroxy-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)formamide.To a mixture of said compound with trifluoroacetic acid (5 mL) was addedtriethylsilane (0.5 mL, 3.2 mmol) with ice-cooling, and the mixture wasstirred at room temperature for 30 minutes. The reaction solution wasconcentrated under reduced pressure, and to the residue was added asaturated sodium hydrogen carbonate solution to alkalify the aqueouslayer, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. To a solution ofthe obtained residue in methanol (20 mL) was added concentratedhydrochloric acid (10 ml), and the mixture was heated under reflux for 2hours. The solvent was distilled off under reduced pressure and theresidue was neutralized with a 12 N aqueous sodium hydroxide solution.After extracting with ethyl acetate, the organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate 4:1) to obtain440 mg (yield 62%) of the title compound. Melting point: 75-76° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.26 (3H, s), 1.40 (3H, s), 1.79 (3H, s), 1.98 (3H,s), 2.05 (3H, s), 2.74 (1H, dd, J=14.4, 5.7 Hz), 2.88 (1H, dd, J=14.4,8.4 Hz), 3.25 (1H, dd, J=14.4, 8.4 Hz), 3.53 (2H, br s), 7.10-7.28 (5H,m).

REFERENCE EXAMPLE 805-Amino-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-3-ol

To a solution of 4-bromotoluene (2.73 g, 16.0 mmol) in THF (30 mL) wasadded dropwise a solution of n-butyllithium in hexane (1.60 M, 10.0 mL,16.0 mmol) under argon atmosphere at −78° C., and the mixture wasstirred at the same temperature for 30 minutes. Then, to the reactionsolution was added dropwise a solution of5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 57 (1.0 g, 4.56 mmol) in THF (10 mL) at the sametemperature, and the reaction solution was stirred at room temperaturefor 1 hour, followed by addition of water, which was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=10:1), to obtain 921 mg (yield 65%)of the title compound. Melting point: 165-166° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.85 (3H, s), 1.50 (3H, s), 1.83 (3H, s), 2.11 (1H,s), 2.14 (3H, s), 2.18 (3H, s), 2.34 (3H, s), 3.31 (2H, br s), 6.80-7.70(4H, m).

REFERENCE EXAMPLE 815-Amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-ol

Using 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one obtained inReference Example 57 and 2-bromonaphthalene, the title compound wassynthesized in the same manner as in Reference Example 80. Yield 66%.Melting point: 121-122° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.88 (3H, s), 1.56 (3H, s), 1.79 (3H, s), 2.16 (3H,s), 2.22 (3H, s), 2.42 (1H, s), 3.32 (2H, br s), 7.07-7.21 (1H, m),7.37-8.00 (5H, m), 8.16-8.31 (1H, m).

REFERENCE EXAMPLE 821-(4-Isopropylphenyl)-1-(2-methoxyphenyl)-2-methylpropan-1-ol

To a solution of 2-bromoanisole (5.0 g, 26.7 mmol) in THF (50 mL) wasadded n-butyllithium (1.6 M, 18 mL, 29 mmol) at −78° C., and the mixturewas stirred at the same temperature for 30 minutes. To the reactionsolution was added 1-(4-isopropylphenyl)-2-methylpropan-1-one (5.70 g,30.0 mmol), and the mixture was stirred at room temperature for 1 hour.Water was poured into the reaction mixture which was extracted withethyl acetate, and the combined organic layer was washed with water,dried over magnesium sulfate, filtered and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=20:1) to obtain 3.4 g (yield 43%)of the title compound. Melting point: 85-86° C. (methanol).

¹H-NMR (CDCl₃) δ: 0.76 (3H, d, J=6.9 Hz), 0.94 (3H, d, J=6.9 Hz), 1.20(6H, d, J=6.9 Hz), 2.68 (1H, septet, J=6.9 Hz), 2.83 (1H, septet, J=6.9Hz), 3.59 (3H, s), 4.91 (1H, s), 6.82 (1H, d, J=8.1 Hz), 6.99 (1H, dt,J=7.5, 1.5 Hz), 7.06 (2H, d, J=7.5 Hz), 7.13-7.25 (3H, m), 7.52 (1H, dd,J=7.5, 1.5 Hz).

REFERENCE EXAMPLE 833-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran

A mixture of1-(4-isopropylphenyl)-1-(2-methoxyphenyl)-2-methylpropan-1-ol obtainedin Reference Example 82 (3.4 g, 11.4 mmol), 48% hydrobromic acid (50 mL)and acetic acid (10 mL) was heated under reflux under argon atmospherefor 16 hours. After cooling, water was added to the reaction solution,which was extracted with ethyl acetate, and the combined organic layerwas washed with water, dried over magnesium sulfate, filtered and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=20:1) toobtain 2.71 g (yield 89%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 0.96 (3H, s), 1.24 (6H, d, J=7.2 Hz), 1.59 (3H, s),2.89 (1H, septet, J=7.2 Hz), 4.33 (1H, s), 6.77-6.89 (2H, m), 6.98-7.06(3H, m), 7.12-7.19 (3H, m)

REFERENCE EXAMPLE 845-Bromo-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 83, the title compound was synthesized inthe same manner as in Reference Example 23. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.25 (6H, d, J=6.9 Hz), 1.57 (3H, s),2.89 (1H, septet, J=6.9 Hz), 4.30 (1H, s), 6.69 (1H, d, J=8.2 Hz), 6.99(2H, d, J=8.1 Hz), 7.12-7.28 (4H, m).

REFERENCE EXAMPLE 85N-Benzyl-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 84, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 46%. Melting point:85-86° C. (methanol).

¹H-NMR (CDCl₃) δ: 0.93 (3H, s), 1.25 (6H, d, J=7.0 Hz), 1.57 (3H, s),2.89 (1H, septet, J=7.0 Hz), 3.62 (1H, br s), 4.22 (2H, s), 4.26 (1H,s), 6.40-6.55 (2H, m), 6.68 (1H, d, J=8.2 Hz), 7.02 (2H, d, J=8.0 Hz),7.15 (2H, d, J=8.0 Hz), 7.20-7.40 (5H, m).

REFERENCE EXAMPLE 863-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 85, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 98%. Melting point:109-110° C. (hexane).

¹H-NMR (CDCl₃) δ: 0.94 (3H, s), 1.24 (6H, d, J=6.9 Hz), 1.55 (3H, s),2.89 (1H, septet, J=6.9 Hz), 3.33 (2H, br s), 4.23 (1H, s), 6.44 (1H, d,J=2.1 Hz), 6.52 (1H, d, J=8.1, 2.1 Hz), 6.63 (1H, d, J=8.2 Hz), 7.02(2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 871-Isopropyl-4-(2-methyl-3-(4-methylphenoxy)propene-1-yl)benzene

To a solution of p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL) was addedsodium hydride (a 60% liquid paraffin dispersion, 1.42 g, 35.5 mmol)under nitrogen atmosphere at 0° C., and the mixture was stirred at thesame temperature for 30 minutes. To the reaction solution was added1-(3-bromo-2-methyl-1-propenyl)-4-isopropyl benzene (9.0 g, 35.5 mmol),and the mixture was stirred at room temperature for 3 hours. Water wasadded to the reaction solution, and the product was extracted withdiisopropyl ether. The extract was washed with water, dried overmagnesium sulfate, and then concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=20:1) to obtain 8.20 g (yield 91%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.6 Hz), 1.98 (3H, s), 2.21 (3H, s),2.90 (1H, septet, J=7.0 Hz), 4.53 (2H, s), 6.58 (1H, s), 6.86 (2H, d,J=8.8 Hz), 7.08 (2H, d, J=8.8 Hz), 7.14-7.25 (4H, m).

REFERENCE EXAMPLE 884-((3-(4-Isopropylphenyl)-2-methyl-2-propenyl)oxy)-2,6-dimethylphenylacetate

Using 4-hydroxy-2,6-dimethylphenyl acetate, the title compound wassynthesized in the same manner as in Reference Example 87. Yield 83%.Oily matter.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=7.2 Hz), 1.97 (3H, s), 2.12 (6H, s),2.32 (3H, s), 2.90 (1H, septet, J=7.2 Hz), 4.49 (2H, s), 6.57 (1H, s),6.66 (2H, s), 7.18-7.25 (4H, m).

REFERENCE EXAMPLE 892-(1-(4-Isopropylphenyl)-2-methyl-2-propenyl)-4-methylphenol

A solution of1-isopropyl-4-(2-methyl-3-(4-methylphenoxy)propene-1-yl)benzene obtainedin Reference Example 87 (8.2 g, 29.2 mmol) in N,N-dimethylaniline (50mL) was stirred under argon atmosphere at 215° C. for 16 hours. Aftercooling, the reaction mixture was diluted with diisopropyl ether, washedwith 5 N hydrochloric acid and water, dried over magnesium sulfate, andthen concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to obtain 7.80 g (yield 95%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=7.2 Hz), 1.83 (3H, s), 2.22 (3H, s),2.89 (1H, septet, J=7.2 Hz), 4.61 (1H, s), 4.75 (1H, s), 5.04 (1H, s),5.12 (1H, s), 6.70-6.78 (2H, m), 6.94 (1H, d, J=8.0 Hz), 7.09 (2H, d,J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 903-(4-Isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran

Using 2-(1-(4-isopropylphenyl)-2-methyl-2-propenyl)-4-methylphenolobtained in Reference Example 89, the title compound was synthesized inthe same manner as in Reference Example 83. Yield 37%. Melting point:65-66° C.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.25 (6H, d, J=6.9 Hz), 1.57 (3H, s),2.25 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 4.28 (1H, s), 6.71 (1H, d,J=8.1 Hz), 6.86 (1H, s), 6.93-7.03 (3H, m), 7.15 (2H, d, J=7.8 Hz).

REFERENCE EXAMPLE 913-(4-Isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran

A solution of4-((3-(4-isopropylphenyl)-2-methylpropene-2-yl)oxy)-2,6-dimethylphenylacetate obtained in Reference Example 88 (6.3 g, 17.9 mmol) inN,N-dimethylaniline (30 mL) was stirred under argon atmosphere at 215°C. for 16 hours. After cooling, the reaction mixture was diluted withdiisopropyl ether, washed with 5 N hydrochloric acid and water, driedover magnesium sulfate, and then concentrated under reduced pressure. Amixture of the obtained residue and 48% hydrobromic acid (30 mL)-aceticacid (5 mL) was heated under reflux under argon atmosphere for 16 hours.After cooling, water was added to the reaction solution, which wasextracted with ethyl acetate, and the combined organic layer was washedwith water, dried over magnesium sulfate, filtered and then concentratedunder reduced pressure. To a solution of the obtained residue in DMF (30mL) was added sodium hydride (a 60% liquid paraffin dispersion, 556 mg,13.9 mmol) under nitrogen atmosphere at 0° C., and the mixture wasstirred at the same temperature for 30 minutes. To the reaction solutionwas added methyl iodide (1.97 g, 13.9 mmol), and the mixture was stirredat room temperature for 3 hours. To the reaction solution, is addedwater, and the product was extracted with ethyl acetate. The combinedextract was washed with water, dried over magnesium sulfate, andconcentrated under reduced pressure, and the obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1)to obtain 2.10 g (yield 36%) of the title compound as an oily matter.Melting point: 121-123° C. (methanol).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.22 (6H, d, J=7.2 Hz), 1.49 (3H, s),1.85 (3H, s), 2.27 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.63 (3H, s),4.06 (1H, s), 6.49 (1H, s), 6.51-7.11 (4H, m).

REFERENCE EXAMPLE 927-Bromo-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 90, the title compound was synthesized inthe same manner as in Reference Example 18. Yield 86%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.25 (6H, d, J=6.9 Hz), 1.61 (3H, s),2.23 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 4.35 (1H, s), 6.77 (1H, s),6.99 (2H, d, J=8.1 Hz), 7.10-7.21 (3H, m).

REFERENCE EXAMPLE 937-Bromo-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran

Using3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 91, the title compound was synthesized inthe same manner as in Reference Example 18. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 1.05 (3H, s), 1.23 (6H, d, J=7.0 Hz), 1.53 (3H, s),1.82 (3H, s), 2.36 (3H, s), 2.86 (1H, septet, J=7.0 Hz), 3.62 (3H, s),4.08 (1H, s), 6.60-7.20 (4H, m).

REFERENCE EXAMPLE 94N-Benzyl-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine

Using7-bromo-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 92, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 79%. Melting point:80-81° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.94 (3H, s), 1.24 (6H, d, J=6.9 Hz), 1.56 (3H, s),2.20 (3H, s), 2.89 (1H, septet, J=6.9 Hz), 4.01 (1H, br s), 4.28 (2H,s), 4.37 (1H, s), 6.27 (1H, s), 6.37 (1H, s), 7.02 (2H, d, J=8.1 Hz),7.14 (2H, d, J=8.1 Hz), 7.21-7.44 (5H, m).

REFERENCE EXAMPLE 95N-Benzyl-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine

Using7-bromo-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 93, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 79%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.98 (3H, s), 1.22 (6H, d, J=6.9 Hz), 1.44 (3H, s),1.78 (3H, s), 2.14 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.42-3.67 (4H,m), 4.01 (1H, s), 4.35 (1H, d, J=14.4 Hz), 4.42 (1H, d, J=14.4 Hz),6.50-7.18 (4H, m), 7.20-7.38 (5H, m).

REFERENCE EXAMPLE 963-(4-Isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine

UsingN-benzyl-3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amineobtained in Reference Example 94, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 65%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.24 (6H, d, J=7.2 Hz), 1.56 (3H, s),2.18 (3H, s), 2.88 (1H, septet, J=7.2 Hz), 3.50 (2H, br s), 4.26 (1H,s), 6.31 (1H, s), 6.43 (1H, s), 7.02 (2H, d, J=8.1 Hz), 7.14 (2H, d,J=8.1 Hz).

REFERENCE EXAMPLE 973-(4-Isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine

UsingN-benzyl-3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amineobtained in Reference Example 95, the title compound was synthesized inthe same manner as in Reference Example 30.

Yield 83%. Melting point: 111-112° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.22 (6H, d, J=6.9 Hz), 1.50 (3H, s),1.78 (3H, s), 2.14 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.44 (2H, brs), 3.60 (3H, s), 4.08 (1H, s), 6.62-7.11 (4H, m).

REFERENCE EXAMPLE 98N-Benzyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine

To a solution of5-(benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained inReference Example 51 (8.5 g, 28.8 mmol) in methanol (20 mL) was addedsodium borohydride (2.18 g, 57.6 mmol) at room temperature, and themixture was stirred for 2 hours. The reaction solution was concentratedunder reduced pressure, and the residue was extracted with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtain thecrude product,5-(benzylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3-ol. To amixture of said compound with trifluoroacetic acid (30 mL) was addedtriethylsilane (10 mL, 64 mmol) with ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The reaction solution wasconcentrated under reduced pressure, and to the residue was added asaturated sodium hydrogen carbonate solution to alkalify the aqueouslayer, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was crystallized with ethyl acetate-hexane to obtain 4.1 g(yield 51%) of the title compound. Melting point: 80-81° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.47 (6H, s), 2.18 (3H, s), 2.23 (3H, s), 2.83 (1H, brs), 2.91 (2H, s), 3.96 (2H, s), 6.43 (1H, s), 7.25-7.42 (5H, m).

REFERENCE EXAMPLE 99 Ethyl 3-(4-isopropylphenyl)-2-methylacrylate

To a suspension of sodium hydride (a 60% liquid paraffin dispersion,5.92 g, 148 mmol) in DMF (150 mL) was added triethyl2-phosphonopropionate (35.0 g, 148 mmol) at 0° C., and the mixture wasstirred at the same temperature for 10 minutes. To the reaction solutionwas added 4-isopropylbenzaldehyde (20.0 g, 135 mmol), and the mixturewas stirred at room temperature 30 minutes. Water was added to thereaction solution, and the product was extracted twice with ethylacetate. The combined extract was washed with water, dried overmagnesium sulfate, and then concentrated under reduced pressure toobtain 30.1 g (yield 96%) of the oily title compound.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=7.0 Hz), 1.35 (3H, t, J=7.0 Hz), 2.13(3H, s), 2.92 (1H, septet, J=7.0 Hz), 4.27 (2H, q, J=7.0 Hz), 7.21-7.38(4H, m), 7.67 (1H, s).

REFERENCE EXAMPLE 100 Ethyl 2-methyl-3-(4-methylphenyl)acrylate

Using 4-methylbenzaldehyde, the title compound was synthesized in thesame manner as in Reference Example 99.

Yield 91%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.34 (3H, t, J=7.0 Hz), 2.12 (3H, d, J=1.4 Hz), 2.37(3H, s), 4.26 (2H, q, J=7.0 Hz), 7.19 (2H, d, J=8.4 Hz), 7.31 (2H, d,J=8.4 Hz), 7.66 (1H, s).

REFERENCE EXAMPLE 101 Ethyl 3-(4-fluorophenyl)-2-methylacrylate

Using 4-fluorobenzaldehyde, the title compound was synthesized in thesame manner as in Reference Example 99.

Yield 97%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.35 (3H, t, J=7.0 Hz), 2.10 (3H, d, J=1.2 Hz), 4.28(2H, q, J=7.0 Hz), 7.08 (2H, t, J=8.8 Hz), 7.32-7.43 (2H, m), 7.65 (1H,s).

REFERENCE EXAMPLE 102 Ethyl(E)-3-(4-isopropylphenyl)-2-acrylate

To a suspension of sodium hydride (a 60% liquid paraffin dispersion,10.4 g, 260 mmol) in DMF (200 mL) was added triethyl phosphonoacetate(58.2 g, 236 mmol) at 0° C., and the mixture was stirred at the sametemperature for 10 minutes. To the reaction solution was added4-isopropylbenzaldehyde (35.0 g, 260 mmol) and the mixture was stirredat room temperature for 30 minutes. Water was added to the reactionsolution, and the product was twice extracted with ethyl acetate. Thecombined extract was washed with water, dried over magnesium sulfate andthen concentrated under reduced pressure to obtain the oily titlecompound 47.5 g (yield 92%).

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz), 2.92(1H, septet, J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz), 6.40 (1H, d, J=15.8 Hz),7.24 (2H, d, J=8.2 Hz), 7.46 (2H, d, J=8.2 Hz), 7.67 (1H, d, J=15.8 Hz).

REFERENCE EXAMPLE 103 3-(4-Isopropylphenyl)-2-methyl-2-propen-1-ol

To a suspension of ethyl 3-(4-isopropylphenyl)-2-methyl-2-acrylate (9.00g, 38.7 mmol) obtained in Reference Example 99 and cerous chloride (1.00g, 4.06 mmol) in THF (50 mL) was added lithium aluminum hydride (1.47 g,38.7 mmol) in four batches for 30 minutes, and the mixture was stirredat the same temperature for 30 minutes. Water was added to the reactionsolution, and the product was twice extracted with ethyl acetate. Thecombined extract was washed with water, dried over magnesium sulfate,and then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=8:1) to obtainthe oily title compound 6.30 g (yield 86%).

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=7.0 Hz), 1.91 (3H, d, J=1.4 Hz), 2.90(1H, septet, J=7.0 Hz), 4.17 (2H, d, J=0.8 Hz), 6.49 (1H, dd, J=2.6, 1.4Hz), 7.15-7.25 (4H, m), 1H unidentified

REFERENCE EXAMPLE 104 2-Methyl-3-(4-methylphenyl)-2-propen-1-ol

Using ethyl 2-methyl-3-(4-methylphenyl)-2-acrylate synthesized inReference Example 100, the title compound was synthesized in the samemanner as in Reference Example 103. Yield 42%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.87 (3H, s), 2.32 (3H, s), 4.13 (2H, s), 6.46 (1H,s), 7.08-7.22 (4H, m), 1H unidentified

REFERENCE EXAMPLE 105 3-(4-Fluorophenyl)-2-methyl-2-propen-1-ol

Using ethyl 3-(4-fluorophenyl)-2-methyl-2-acrylate synthesized inReference Example 101, the title compound was synthesized in the samemanner as in Reference Example 103. Yield 95%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.98 (3H, d, J=1.6 Hz), 4.11 (2H, s), 6.58 (1H, s),7.01 (2H, t, J=8.8 Hz), 7.18-7.28 (2H, m), 1H unidentified

REFERENCE EXAMPLE 106 3-(4-Bromophenyl)-2-methyl-2-propen-1-ol

To a solution of sodium tert-butoxide (10.6 g, 110 mmol) in DMF (60 mL)was added triethyl phosphonoacetate (26.2 g, 110 mmol) under argonatmosphere at −10° C. and the mixture was stirred at the sametemperature for 1 hour. 4-bromobenzaldehyde (18.5 g, 100 mmol) was addedto the solution at 10° C. or lower, and the mixture was warmed to roomtemperature, and then stirred for 2 hours. Water was added to thereaction solution after ice-cooling, which was extracted with toluene.The extract was washed with a saturated brine, dried over sodiumsulfate, and then concentrated under reduced pressure. The obtained oilymatter was dissolved in toluene (200 mL), dihydrobis(2-methoxyethoxy)sodium aluminate (a 70% toluene solution, 41.5 g, 144 mmol) was addeddropwise at −10° C., and then the mixture was stirred at the sametemperature for 1 hour. A 10% aqueous potassium sodium tartrate solutionwas added to separate the organic layer. The organic layer was washedwith a 10% aqueous potassium sodium tartrate solution and a saturatedbrine, dried over sodium sulfate, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=2:1) to obtain 20.1 g (yield 88%)of the title compound as an oily matter.

¹H-NMR (CDCl₃) δ: 1.54 (1H, t, J=6.0 Hz), 1.87 (3H, d, J=1.2 Hz), 4.19(2H, d, J=6.0 Hz), 6.46 (1H, s), 7.14 (2H, d, J=8.4 Hz), 7.45 (2H, d,J=8.4 Hz).

REFERENCE EXAMPLE 107 (E)-3-(4-Isopropylphenyl)-2-propen-1-ol

Using ethyl(E)-3-(4-isopropylphenyl)-2-acrylate synthesized in ReferenceExample 102, the title compound was synthesized in the same manner as inReference Example 103. Yield 65%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.0 Hz), 2.79-3.00 (2H, m), 4.30 (2H,d, J=5.6 Hz), 6.35 (1H, dt, J=15.8, 5.6 Hz), 6.59 (1H, d, J=15.8 Hz),7.10-7.39 (4H, m).

REFERENCE EXAMPLE 108 1-(3-Bromo-2-methyl-1-propenyl)-4-isopropylbenzene

To a solution of 3-(4-isopropylphenyl)-2-methyl-2-propen-1-olsynthesized in Reference Example 103 (6.30 g, 33.1 mmol) in isopropylether (50 mL) was added phosphorus tribromide (5.98 g, 22.1 mmol) withice-cooling and the mixture was stirred at room temperature for 30minutes. Water was added to the reaction solution and the mixture wasextracted with isopropyl ether. The organic layer was washed with waterand a saturated sodium hydrogen carbonate solution, dried over magnesiumsulfate, filtered, and then concentrated under reduced pressure toobtain the oily title compound 7.63 g (yield 91%)

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=7.0 Hz), 2.03 (3H, d, J=1.4 Hz), 2.90(1H, septet, J=7.0 Hz), 4.15 (2H, d, J=0.8 Hz), 6.62 (1H, s), 7.14-7.26(4H, m).

REFERENCE EXAMPLE 109 1-(3-Bromo-2-methyl-1-propenyl)benzene

Using 2-methyl-3-phenyl-2-propen-1-ol, the title compound wassynthesized in the same manner as in Reference Example 108. Yield 89%.Oily matter.

¹H-NMR (CDCl₃) δ: 2.01 (3H, d, J=1.4 Hz), 4.13 (2H, d, J=0.8 Hz), 6.64(1H, s), 7.19-7.44 (5H, m).

REFERENCE EXAMPLE 110 1-(3-Bromo-2-methyl-1-propenyl)-4-methylbenzene

Using 2-methyl-3-(4-methylphenyl)-2-propen-1-ol synthesized in ReferenceExample 104, the title compound was synthesized in the same manner as inReference Example 108. Yield 80%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.01 (3H, s), 2.34 (3H, s), 4.13 (2H, s), 6.60 (1H,s), 7.09-7.22 (4H, m).

REFERENCE EXAMPLE 111 1-(3-Bromo-2-methyl-1-propenyl)-4-fluorobenzene

Using 3-(4-fluorophenyl)-2-methyl-2-propen-1-ol synthesized in ReferenceExample 105, the title compound was synthesized in the same manner as inReference Example 108. Yield 79%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.87 (3H, s), 4.17 (2H, s), 6.48 (1H, s), 7.01 (2H, t,J=8.8 Hz), 7.18-7.27 (2H, m).

REFERENCE EXAMPLE 112 1-Bromo-4-(3-bromo-2-methyl-1-propenyl)benzene

To an acetonitrile solution (180 mL) of triphenylphosphine (24.3 g, 92.7mmol) was added dropwise bromine (4.78 mL, 185 mmol) at 0° C. and themixture was stirred at the same temperature for 30 minutes. To thesolution was added the acetonitrile solution (60 mL) of3-(4-bromophenyl)-2-methyl-2-propen-1-ol obtained in Reference Example106 (20.1 g, 88.3 mmol) and the mixture was stirred at 0° C. for 1 hour.The reaction solution was concentrated under reduced pressure, diethylether (200 mL) was added to the residue, and the insolubles werefiltered off. The solution was washed with a saturated brine, dried oversodium sulfate, and then concentrated under reduced pressure to obtain25.0 g (yield 98%) of the title compound as an oily matter.

¹H-NMR (CDCl₃) δ: 1.99 (3H, d, J=1.4 Hz), 4.12 (2H, s), 6.57 (1H, s),7.15 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 113 1-((E)-3-Bromo-1-propenyl)-4-isopropylbenzene

Using (E)-3-(4-isopropylphenyl)-2-propen-1-ol synthesized in ReferenceExample 107, the title compound was synthesized in the same manner as inReference Example 108. Yield 72%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.24 (6H, d, J=7.0 Hz), 2.89 (1H, septet, J=7.0 Hz),4.16 (2H, dd, J=7.8, 0.8 Hz), 6.35 (1H, dt, J=15.4, 7.8 Hz), 6.63 (1H,d, J=15.4 Hz), 7.14-7.35 (4H, m).

REFERENCE EXAMPLE 114N-(4-((3-(4-Isopropylphenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamide

To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (3.00 g,16.7 mmol) in DMF (30 mL) was added sodium hydride (a 60% liquidparaffin dispersion, 0.74 g, 18.4 mmol) under nitrogen atmosphere at 0°C., and the mixture was stirred at the same temperature for 10 minutes.To the reaction solution was added1-(3-bromo-2-methyl-1-propenyl)-4-isopropylbenzene synthesized inReference Example 108 (4.66 g, 18.4 mmol) and the mixture was stirred atroom temperature for 30 minutes. Water was added to the reactionsolution and the product was twice extracted with ethyl acetate. Thecombined extract was washed with water, dried over magnesium sulfate,and then concentrated under reduced pressure. The obtained residue wascrystallized from ethyl acetate-hexane to obtain 3.70 g (yield 63%) ofthe title compound. Melting point: 153-155° C.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=7.0 Hz), 2.00 (3H, s), 2.07-2.34 (9H,m), 2.91 (1H, septet, J=7.0 Hz), 4.54 (2H, d, J=5.4 Hz), 6.59-6.84 (3H,m), 7.17-7.36 (4H, m), 7.98 (0.5H, d, J=12.0 Hz), 8.41 (0.5H, s).

REFERENCE EXAMPLE 115N-(2,3,6-Trimethyl-4-((2-methyl-3-phenyl-2-propenyl)oxy)phenyl)formamide

Using 1-(3-bromo-2-methyl-1-propenyl)benzene synthesized in ReferenceExample 109, the title compound was synthesized in the same manner as inReference Example 114. Yield 41%. Melting point: 152-154° C. (ethylacetate-hexane)

¹H-NMR (CDCl₃) δ: 1.98 (3H, d, J=1.6 Hz), 2.10-2.32 (9H, m), 4.54 (2H,d, J=5.2 Hz), 6.65 (1H, s), 6.67 (1H, s), 6.69-6.90 (1H, m), 7.11-7.41(5H, m), 7.98 (0.5H, d, J=12.0 Hz), 8.41 (0.5H, d, J=1.4 Hz).

REFERENCE EXAMPLE 116N-(2,3,6-Trimethyl-4-((2-methyl-3-(4-methylphenyl)-2-propenyl)oxy)phenyl)formamide

Using 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene synthesized inReference Example 110, the title compound was synthesized in the samemanner as in Reference Example 114. Yield 44%. Melting point: 167-169°C.

¹H-NMR (CDCl₃) δ: 1.98 (3H, s), 2.07-2.38 (9H, m), 2.35 (3H, s), 4.53(2H, d, J=6.6 Hz), 6.61 (1H, s), 6.66 (1H, d, J=2.4 Hz), 6.82-7.09 (1H,m), 7.11-7.31 (4H, m), 7.98 (0.5H, d, J=12.2 Hz), 8.3.8 (0.5H, s).

REFERENCE EXAMPLE 117N-(4-((3-(4-Fluorophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamide

Using 1-(3-bromo-2-methyl-1-propenyl)-4-fluorobenzene synthesized inReference Example 111, the title compound was synthesized in the samemanner as in Reference Example 114. Yield 52%. Melting point: 164-165°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.96 (3H, s), 2.12-2.32 (9H, m), 4.53 (2H, d, J=5.2Hz), 6.60 (1H, s), 6.66 (1H, s), 6.71-6.95 (1H, m), 7.04 (2H, t, J=8.8Hz), 7.22-7.33 (2H, m), 8.04 (0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.4Hz).

REFERENCE EXAMPLE 118N-(4-((3-(4-Bromophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamide

Using 1-bromo-4-(3-bromo-2-methyl-1-propenyl)benzene synthesized inReference Example 112, the title compound was synthesized in the samemanner as in Reference Example 114. Yield 79%.

¹H-NMR (CDCl₃) δ: 1.95-1.97 (3H, m), 2.18-2.27 (9H, m), 4.52 (2H, br d,J=4.4 Hz), 6.58 (1H, br s), 6.65 (1H, br s), 6.78 (1H, br d, J=15.0 Hz),7.17 (2H, d, J=8.2 Hz), 7.47 (2H, d J=8.2 Hz), 7.99 (0.5H, d, J=8.1 Hz),8.42 (0.5H, d, J=1.5 Hz).

REFERENCE EXAMPLE 119N-(4-(((E)-3-(4-Isopropylphenyl)-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamide

Using 1-((E)-3-bromo-1-propenyl)-4-isopropylbenzene synthesized inReference Example 113, the title compound was synthesized. Yield 59%.Melting point: 165-167° C. (ethyl acetate-hexane)

¹H-NMR (CDCl₃) δ: 1.25 (6H, d, J=6.8 Hz), 2.13-2.27 (9H, m), 2.90 (1H,septet, J=6.8 Hz), 4.66 (2H, t, J=5.8 Hz), 6.37 (1H, dt, J=15.8, 5.8Hz), 6.65-6.88 (3H, m), 7.16-7.26 (2H, m), 7.35 (2H, d, J=8.0 Hz), 7.98(0.5H, d, J=12.0 Hz), 8.40 (0.5H, d, J=1.4 Hz).

REFERENCE EXAMPLE 1203-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine

A solution ofN-(4-((3-(4-isopropylphenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamidesynthesized in Reference Example 114 (3.70 g, 10.5 mmol) inN,N-dimethylaniline (20 mL) was stirred under argon atmosphere at 215°C. for 6 hours. After cooling, the reaction mixture was extracted withethyl acetate, washed with 2 N hydrochloric acid and water, dried overmagnesium sulfate, and then concentrated under reduced pressure toobtain the crude product ofN-(4-hydroxy-3-(1-(4-isopropylphenyl)-2-methyl-2-propenyl)-2,5,6-trimethylphenyl)formamide.A mixture of this compound (2.98 g, 8.47 mmol) and concentratedhydrochloric acid (20 mL)-methanol (60 mL) was heated under reflux undernitrogen atmosphere for 2 hours. The solvent was concentrated underreduced pressure, and the obtained residue was neutralized with a 8 Naqueous sodium hydroxide solution. The product was twice extracted withethyl acetate. The combined extract was washed with water, dried overmagnesium sulfate, and then concentrated under reduced pressure. Theobtained residue was crystallized from isopropyl ether-hexane to obtain2.23 g (yield 66%) of the title compound. Melting point: 130-132° C.

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.21 (6H, d, J=6.6 Hz), 1.47 (3H, s),1.78 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.40-2.60 (3H, m), 4.08 (1H,s), 6.72-7.00 (2H, m), 7.07 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 1212,2,4,6,7-Pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-(2,3,6-trimethyl-4-((2-methyl-3-phenyl-2-propenyl)oxy)phenyl)formamidesynthesized in Reference Example 115, the title compound was synthesizedin the same manner as in Reference Example 120. Yield 67%. Meltingpoint: 129-131° C.

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.48 (3H, s), 1.77 (3H, s), 2.13 (3H,s), 2.19 (3H, s), 3.20 (2H, br s), 4.12 (1H, s), 6.70-7.30 (5H, m).

REFERENCE EXAMPLE 1222,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

UsingN-(2,3,6-trimethyl-4-((2-methyl-3-(4-methylphenyl)-2-propenyl)oxy)phenyl)formamidesynthesized in Reference Example 116, the title compound was synthesizedin the same manner as in Reference Example 120.

Yield 57%. Melting point: 114-115° C. (petroleum ether).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H,s), 2.19 (3H, s), 2.30 (3H, s), 3.23 (2H, br s), 4.08 (1H, s), 6.60-7.23(4H, m).

REFERENCE EXAMPLE 1233-(4-Fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-(4-((3-(4-fluorophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamidesynthesized in Reference Example 117, the title compound was synthesizedin the same manner as in Reference Example 120.

Yield 78%. Melting point: 125-127° C. (petroleum ether).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H,s), 2.19 (3H, s), 3.10 (2H, br s), 4.09 (1H, s), 6.62-7.20 (4H, m).

REFERENCE EXAMPLE 1243-(4-Bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-(4-((3-(4-bromophenyl)-2-methyl-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamidesynthesized in Reference Example 118, the title compound was synthesizedin the same manner as in Reference Example 120.

Yield 56%.

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H,s), 2.18 (3H, s), 3.23 (2H, br), 4.07 (1H, s), 6.83 (2H, br), 7.36 (2H,brd, J=8.0 Hz).

REFERENCE EXAMPLE 125N-(4-Hydroxy-3-(1-(4-isopropylphenyl)-2-propenyl)-2,5,6-trimethylphenyl)formamide

A solution ofN-(4-(((E)-3-(4-isopropylphenyl)-2-propenyl)oxy)-2,3,6-trimethylphenyl)formamidesynthesized in Reference Example 119 (5.80 g, 17.2 mmol) inN,N-dimethylaniline (50 mL) was stirred under argon atmosphere at 215°C. for 6 hours. After cooling, the reaction mixture was diluted withethyl acetate, was washed with 2 N hydrochloric acid and water, driedover magnesium sulfate, and then concentrated under reduced pressure.The residue was crystallized from ethyl acetate to obtain 3.50 g (yield60%) of the title compound. Melting point: 170-171° C.

¹H-NMR (CDCl₃) δ: 1.18-1.40 (6H, m), 2.11-2.27 (9H, m), 2.77-3.00 (1H,m), 5.00-5.22 (2H, m), 5.30-5.42 (1H, m), 6.30-6.85 (2H, m), 7.10-7.37(5H, m), 7.97 (0.5H, d, J=12.2 Hz), 8.43 (0.5H, d, J=1.4 Hz).

REFERENCE EXAMPLE 1263-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-aminehydrochloride

To a suspension ofN-(4-hydroxy-3-(1-(4-isopropylphenyl)-2-propenyl)-2,5,6-trimethylphenyl)formamidesynthesized in Reference Example 125 (3.50 g, 10.4 mmol) and calciumcarbonate (1.35 g, 13.5 mmol) in THF (15 mL)-methanol (15 mL) was addedslowly benzyltrimethylammonium iododichloride (3.90 g, 11.4 mmol). Thereaction solution was stirred at room temperature for 30 minutes. Afterseparating the insolubles, the solvent was concentrated under reducedpressure, and ethyl acetate and water were added to the residue. Theorganic layer was separated and an aqueous layer was twice extractedwith ethyl acetate. The combined organic layer was washed with a 10%sodium hydrosulfite aqueous solution, water, a saturated sodium hydrogencarbonate solution and a saturated brine, dried over magnesium sulfate,and then concentrated under reduced pressure to obtain 4.08 g ofN-(2-iodomethyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide.A solution of this compound (4.08 g, 8.81 mmol) and1,8-diazabicyclo(5,4,0)-7-undecene (6.58 mL, 44.0 mmol) in toluene (30mL) was stirred at 100° C. under argon atmosphere for 3 hours. Water wasadded to the reaction solution, which was twice extracted with ethylacetate. The extract was washed with 2 N hydrochloric acid and water,dried over magnesium sulfate, and then concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=20:1) to obtainN-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl)formamide2.40 g. A mixture of this compound (2.40 g, 7.18 mmol) in hydrochloricacid (20 ml)-methanol (60 mL) was heated under reflux under nitrogenatmosphere for two hours. The solvent was concentrated under reducedpressure, and the obtained residue was neutralized with 8 N aqueoussodium hydroxide solution. The product was twice extracted with ethylacetate. The combined extract was washed with water, dried overmagnesium sulfate, and then concentrated under reduced pressure toobtain the oily free base 1.80 g. The oily free base (0.50 g, 1.63 mmol)was dissolved in hydrochloric acid-methanol solution, the solvent wasconcentrated under reduced pressure, and the obtained residue wascrystallized by methanol to obtain the object compound 0.41 g (yield41%). Melting point: 194-197° C.

¹H-NMR (CDCl₃) δ: 1.29 (6H, d, J=7.0 Hz), 2.30 (6H, s), 2.41 (3H, s),2.60 (3H, s), 2.94 (1H, septet, J=7.0 Hz), 7.13-7.26 (4H, m), 10.1 (2H,br s), 1H unidentified

REFERENCE EXAMPLE 127 4-Methoxy-2,3,6-trimethylaniline

N-(4-Hydroxy-2,3,6-trimethylphenyl)formamide (30.0 g, 167 mmol) wasdissolved in a mixed solvent of 4 N potassium hydroxide aqueous solution(100 mL) and methanol (300 mL), and dimethyl sulfate (42.0 g, 334 mmol)was added to the solution at room temperature and the mixture was heatedunder reflux for 14 hours. After ice-cooling, the precipitated crystalswere collected by filtration to obtain the crude product ofN-(4-methoxy-2,3,6-trimethylphenyl)formamide. To a suspension of thecompound in methanol (200 mL) was added concentrated hydrochloric acid(50 mL) and the mixture was heated under reflux for 3 hours. Thereaction mixture was cooled to room temperature, and then wasneutralized with a 8 N aqueous sodium hydroxide solution. The productwas twice extracted with ethyl acetate, and the combined extract waswashed with 10% sodium hydrosulfite aqueous solution and water, driedover magnesium sulfate, and then concentrated under reduced pressure.The residue was crystallized from isopropyl ether to obtain the objectcompound 21.0 g (yield 76%). Melting point: 70-72° C.

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.16 (3H, s), 2.18 (3H, s), 3.16 (1H, brs), 3.74 (3H, s), 6.54 (1H, s)

REFERENCE EXAMPLE 128 tert-Butyl4-methoxy-2,3,6-trimethylphenylcarbamate

To a solution of 4-methoxy-2,3,6-trimethylaniline synthesized inReference Example 127 (21.0 g, 127 mmol) and triethylamine (21.0 mL, 152mmol) in THF (150 mL) was added di-tert-butyl dicarbonate (32 mL, 140mmol) at room temperature, and the mixture was heated under reflux for14 hours. The solvent was concentrated under reduced pressure. Water waspoured into the residue, which was twice extracted with ethyl acetate.The combined organic layer was washed with 1 N hydrochloric acid and asaturated sodium hydrogen carbonate solution, dried over magnesiumsulfate, filtered and then concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-hexane to obtain 25.2 g(yield 75%) of the title compound. Melting point: 104-106° C.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.12 (3H, s), 2.17 (3H, s), 2.24 (3H,s), 3.78 (3H, s), 5.81 (1H, br s), 6.58 (1H, s).

REFERENCE EXAMPLE 129 tert-Butyl3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate

To a solution of tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamatesynthesized in Reference Example 128 (12.7 g, 47.9 mmol) and sodiumacetate (4.72 g, 57.5 mmol) in acetic acid (50 mL) was added bromine(8.42 g, 52.7 mmol) at room temperature and the mixture was stirred atthe same temperature for 1 hour. Water (80 mL) was poured into thereaction mixture, and the precipitated crystals were collected byfiltration and then dissolved in ethyl acetate. The solution was washedwith a saturated sodium hydrogen carbonate solution and water, driedover magnesium sulfate, filtered, and then concentrated under reducedpressure. The residue was crystallized from methanol to obtain 15.0 g(yield 91%) of the title compound. Melting point: 159-161° C.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 2.15 (3H, s), 2.24 (3H, s), 2.35 (3H,s), 3.74 (3H, s), 5.92 (1H, br s).

REFERENCE EXAMPLE 1302,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

To a solution of tert-butyl3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate synthesized inReference Example 129 (27.8 g, 80.8 mmol) in THF (150 mL) was addedn-butyllithium (1.6 M, 110 mL, 176 mmol) hexane solution at −78° C. andthe mixture was stirred at the same temperature for 20 minutes.2-Methyl-1-(4-methylphenyl)propane-1-one (13.1 g, 80.7 mmol) was addedto the reaction solution, and the mixture was stirred at roomtemperature for 1 hour. Water (150 mL) was poured into the reactionmixture, which was three times extracted with ethyl acetate, thecombined organic layer was washed with water, dried over magnesiumsulfate, and then concentrated under reduced pressure to obtain thecrude product 26.0 g of tert-butyl3-(1-hydroxy-2-methyl-1-(4-methylphenyl)propyl)-4-methoxy-2,5,6-trimethylphenylcarbamate.A mixture of this compound and 47% hydrobromic acid (100 mL) was heatedunder reflux under argon atmosphere for 4 hours. The reaction mixturewas cooled to room temperature, and then was neutralized with a 8 Naqueous sodium hydroxide solution. The product was twice extracted withethyl acetate, and the combined extract was washed with a saturatedsodium hydrogen carbonate solution, dried over magnesium sulfate, andthen concentrated under reduced pressure. The residue was crystallizedfrom isopropyl ether-hexane to obtain 14.8 g (yield 62%) of the titlecompound. Melting point: 114-115° C.

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H,s), 2.17 (3H, s), 2.30 (3H, s), 2.80 (2H, br s), 4.08 (1H, s), 6.60-7.10(4H, m).

REFERENCE EXAMPLE 131(+)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 130 was subjected to high performanceliquid chromatography (apparatus: Waters Semi-Preparative System,Column:CHIRALCEL OD (20 (i, d)×250 mm) manufactured by Daicel ChemicalIndustries, Ltd., Mobile phase: hexane:isopropanol=95:5, Flow rate: 5mL/min, Column temperature: 30° C., Injection amount: 40 mg), topreparatively separate a fraction with a longer retention time. Meltingpoint: 87-89° C. [α]_(D) ²⁰=+4.7° (c=0.495, methanol).

REFERENCE EXAMPLE 132(−)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 130 was subjected to high performanceliquid chromatography (apparatus: Waters Semi-Preparative System,Column: CHIRALCEL OD (20 (i, d)×250 mm) manufactured by Daicel ChemicalIndustries, Ltd., Moving phase: hexane isopropanol=95:5, Flow rate: 5mL/min, Column temperature: 30° C., Injection amount: 40 mg), topreparatively separate a fraction with a shorter retention time. Meltingpoint: 88-90° C. [α]_(D) ²⁰=−4.3 (c=0.499, methanol).

REFERENCE EXAMPLE 133(+)-3-(4-Bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine

Di-p-toluoyl-D-tartaric acid (3.86 g, 10 mmol) was dissolved inisopropanol (14.2 mL) at 70° C., and a solution of3-(4-bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 124 (3.60 g, 10 mmol) in acetonitrile(47.5 mL) was added dropwise thereto with maintaining the insidetemperature of 60° C. The solution was cooled to 30° C. for 3 hours, andthen was stirred at the same temperature for 2 hours. The precipitatedcrystals were taken, and then were washed with a small amount of coldacetonitrile. The obtained, crude diastereomeric salt was suspended inacetonitrile (29.6 mL) and was stirred over night. The crystals werecollected by filtration, washed with a small amount of coldacetonitrile, and then dried under reduced pressure. The crystals weresuspended in ethyl acetate (100 mL), a saturated sodium hydrogencarbonate solution (100 mL) was added thereto, and the mixture wasstirred thoroughly to separate the organic layer. The organic layer waswashed with water (100 mL) and a saturated brine, and then was driedover anhydrous sodium sulfate. The solvent was dried under reducedpressure, and was crystallized with cold hexane to obtain 1.13 g (yield31%) of the title compound. Melting point: 143-144° C. (hexane). [α]_(D)²⁰=+11.6° (c=0.5, methanol).

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H,s), 2.18 (3H, s), 3.25 (2H, br s), 4.07 (1H, s), 6.85 (2H, br), 7.36(2H, br d, J=6.9 Hz).

REFERENCE EXAMPLE 134(3R)-(+)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 122, the title compound was obtained inthe same manner as in Reference Example 133. Yield 39%. Melting point:87-89° C. (hexane). [α]_(D) ²⁰=+4.7° (c=0.5, methanol).

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H,s), 2.18 (3H, s), 2.30 (3H, s), 2.78 (2H, br), 4.09 (1H, s), 6.83 (2H,br), 7.04 (2H, br d, J=7.4 Hz).

REFERENCE EXAMPLE 1352-(2,3-Dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-ol

To a mixture of 2,3-dimethylphenol (12.2 g, 100 mmol) and potassiumcarbonate (27.4 g, 200 mmol) in dimethylsulfoxide (138 mL) was added2-bromo-1-(4-bromophenyl)-2-methylpropane-1-one (42.2 g, 175 mmol) atroom temperature, and the mixture was warmed to 35° C. The mixture wasstirred at the same temperature for 24 hours, poured into cold water(300 mL), and then extracted with diethyl ether. The organic layer waswashed with a 4 N aqueous sodium hydroxide solution and a saturatedbrine, and then was dried over sodium sulfate. The solvent wasconcentrated under reduced pressure, and then was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:9) to obtain2-(2,3-dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-one of oilymatter. The obtained oily matter was dissolved in methanol (200 mL),sodium borohydride (3.8 g, 100 mmol) was added thereto at 0° C., and themixture was warmed to room temperature. The oily matter was stirred atthe same temperature for 1 hour, cooled to 0° C., and neutralized with 1N hydrochloric acid, and then the solvent was distilled off underreduced pressure. The residue was extracted with ethyl acetate, and theextract solution was washed with a saturated brine, and then was driedover sodium sulfate. The solvent was distilled off under reducedpressure to obtain 17.1 g (yield 60%) of the title compound as an oilymatter.

¹H-NMR (CDCl₃) δ: 1.12 (3H, s), 1.23 (3H, s), 2.19 (3H, s), 2.27 (3H,s), 2.35 (3H, s), 3.38 (1H, d, J=2.0 Hz), 4.88 (1H, d, J=2.0 Hz),6.83-7.07 (3H, m), 7.14 (2H, d, J=8.0 Hz), 7.37 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 1362,2,6,7-Tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran

To a solution of2-(2,3-dimethylphenoxy)-2-methyl-1-(4-methylphenyl)propane-1-olsynthesized in Reference Example 135 (17.0 g, 60 mmol) in toluene (200mL) was added trifluoromethanesulfonate (0.53 mL, 6 mmol) at 0° C., andthe mixture was warmed to 50° C. The mixture was stirred at the sametemperature for 30 minutes and was reacted under reflux condition for 2hours. The reaction solution was cooled to 0° C., and then was pouredinto a saturated sodium hydrogen carbonate solution. The organic layerwas separated, washed with a saturated brine, and dried over sodiumsulfate, and the solvent then was distilled off under reduced pressure.The residue was purified by silica gel column chromatography (ethylacetate:hexane=1:9) to obtain 9.3 g (yield 58%) of the title compound asan oily matter.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.57 (3H, s), 2.16 (3H, s), 2.26 (3H,s), 2.33 (3H, s), 4.29 (1H, s), 6.66 (1H, d, J=7.6 Hz), 6.74 (1H, d,J=7.6, Hz), 6.98 (2H, d, J=8.0 Hz), 7.19 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 1375-Bromo-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran

Using 2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuranobtained in Reference Example 136, the title compound was synthesized inthe same manner as in Reference Example 18. Yield 92%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.55 (3H, s), 2.22 (3H, s), 2.33 (3H,s), 2.34 (3H, s), 4.27 (1H, s), 6.96 (2H, d, J=8.0 Hz), 7.04 (1H, s),7.11 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 138N-Benzyl-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuranobtained in Reference Example 137, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 99%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.92 (3H, s), 1.55 (3H, s), 2.09 (3H, s), 2.21 (3H,s), 2.33 (3H, s), 3.47 (2H, s), 4.17 (1H, s), 4.27 (1H, s), 6.31 (1H,s), 6.97 (2H, d, J=7.8 Hz), 7.09 (2H, d, J=7.8 Hz), 7.20-7.36 (5H, m).

REFERENCE EXAMPLE 1392,2,6,7-Tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

To a solution ofN-benzyl-2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 138 (6.60 g, 17.8 mmol) in ethanol (70 mL)was added 12 N hydrochloric acid (0.1 mL) and 10%-palladium carbon(hydrous 50%, 0.33 g), and the mixture was stirred under hydrogencondition of 5 atmosphere pressure at room temperature for 2 hours. Thecatalyst is filtered off, and the solution was concentrated underreduced pressure. The residue was diluted with ethyl acetate, was washedwith a saturated brine, and then was dried over sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:4)to obtain 4.42 g (yield 88%) of the title compound as an oily matter.

¹H-NMR (CDCl₃) δ: 0.94 (3H, s), 1.54 (3H, s), 2.09 (3H, s), 2.18 (3H,s), 2.33 (3H, s), 3.25 (2H, br), 4.23 (1H, s), 6.30 (1H, s), 7.00 (2H,d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 140N-(3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-aminehydrochloride obtained in Reference Example 126, the title compound wassynthesized in the same manner as in Reference Example 63. Yield 24%.Melting point: 253-254° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.30 (6H, d, J=6.9 Hz), 1.97 (3H, s),2.25 (3H, s), 2.30 (5H, s), 2.43 (3H, s), 2.96 (1H, septet, J=6.9 Hz),6.62 (1H, br s), 7.23 (4H, s).

REFERENCE EXAMPLE 141(+)-(3R)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

A suspension of3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 32 (22.5 g, 80 mmol) and (2S,3S)-(4′-methyl)-tartranilic acid (19.14 g, 80 mmol) in ethanol (480 mL)was heated at 85° C. for dissolution. The solution was cooled to 0° C.for 2 hours, and the precipitated crystals were taken. The crystals werewashed with cold ethanol, and then were dried under reduced pressure.The obtained crystals were suspended in a 2 N aqueous sodium hydroxidesolution (400 mL), which was extracted with diethyl ether. The extractwas washed with a saturated sodium hydrogen carbonate solution and asaturated brine, and then was dried over sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain 9.44 g (yield 34%) of thetitle compound as an oily matter. The obtained oily matter was, ifnecessary, crystallized with cold hexane. Melting point: 53-55° C.[α]_(D) ²⁰=+64.0° (c=0.44, chloroform).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.85 (3H, s), 2.18 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.52 (2H, br), 4.34 (1H, dd, J=4.7, 8.8Hz), 4.50 (1H, dd, J=4.7, 8.8 Hz), 4.76 (1H, t, J=8.8 Hz), 6.56 (1H, s),7.04 (2H, d, J=8.0 Hz), 7.12 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 1421-(4-Isopropylphenyl)-2-(3,5-dimethylphenoxy)ethanone

To a solution of cumene (27.8 mL, 200 mmol) and aluminum chloride (32.0g, 240 mmol) in dichloromethane (300 mL) was added bromoacetylbromide(19.1 mL, 220 mmol) at −10° C., and the mixture was stirred at the sametemperature for 2 hours. The reaction solution was poured into ice-coldwater, and an organic layer was separated. The organic layer was washedwith a saturated sodium hydrogen carbonate solution and a saturatedbrine, and then was dried over sodium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by silica gelcolumn chromatography (ethyl acetate:hexane=1:9) to obtain2-bromo-1-(4-isopropylphenyl)ethanone of oily matter. The obtained oilymatter was added to a solution of 3,5-dimethylphenol (29.3 g, 240 mmol)and potassium carbonate (33.2 g, 240 mmol) in acetone (500 mL), and themixture then was stirred under heat and reflux for 12 hours. Thereaction solution was ice-cooled and poured into cold water, which wasextracted with diethyl ether.

The extract was washed with a saturated brine, and then was dried oversodium sulfate. Then, the solvent was distilled off under the reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4). The obtained oily matter wascrystallized with hexane to obtain 39.4 g (yield 75%) of the titlecompound. Melting point: 68-69° C.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 2.27 (3H, s), 2.28 (3H, s),2.98 (1H, septet, J=6.9 Hz), 5.22 (2H, s), 6.57 (2H, s), 6.63 (1H, s),7.35 (2H, d, J=8.4 Hz), 7.95 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 143 3-(4-Isopropylphenyl)-4,6-dimethylbenzofuran

A solution of 1-(4-isopropylphenyl)-2-(3,5-dimethylphenoxy)ethanoneobtained in Reference Example 142 (38.1 g, 135 mmol) and MontmorilloniteKSF (57.2 g) in toluene (400 mL) was heated at 95° C., and was reactedfor 16 hours. The reaction solution was cooled to room temperature, andthen Montmorillonite KSF was filtered off.

The solution was purified by silica gel column chromatography (ethylacetate:hexane=1:9), and the solvent was distilled off under reducedpressure to obtain 35.6 g (yield 100%) of the title compound as an oilymatter. The oily matter was, if necessary, crystallized with methanol.Melting point: 44-45° C.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.30 (3H, s), 2.43 (3H, s),2.96 (1H, septet, J=6.9 Hz), 6.83 (1H, s), 7.18 (1H, s), 7.25 (2H, d,J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 1443-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

3-(4-Isopropylphenyl)-4,6-dimethyl-1-benzofuran (36.5 g, 135 mmol)obtained in Reference Example 143 and 10%-palladium carbon (50% hydrous,3.7 g) were suspended in ethanol (400 mL), and reductive reaction wasperformed under hydrogen atmosphere of 5 atmospheric pressure at 60° C.for 6 hours. The reaction solution was cooled to room temperature, thecatalyst was filtered off, and the solution was concentrated underreduced pressure. The obtained oily matter was crystallized withmethanol to obtain 27.5 g (yield 77%) of the title compound. Meltingpoint: 48-50° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s), 2.29 (3H, s),2.86 (1H, septet, J=6.9 Hz), 4.35-4.53 (2H, m), 4.83 (1H, t, J=8.1 Hz),6.47 (1H, s), 6.56 (1H, s), 7.04 (2H, d, J=8.2 Hz), 7.13 (2H, d, J=8.2Hz).

REFERENCE EXAMPLE 1453-(4-Methoxyphenyl)-N-(2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-propionamide

Using2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained Reference Example 139 and 3-(4-methoxyphenyl)propionic acid,the title compound was obtained in the same manner as in ReferenceExample 359.

Yield 64%. Melting point: 149-150° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.94 (3H, s), 1.55 (3H, s), 1.98 (3H, s), 2.15 (3H,s), 2.32 (3H, s), 2.58 (2H, d, J=7.5 Hz), 2.94 (2H, d, J=7.5 Hz), 3.73(3H, s), 4.28 (1H, s), 6.63-6.98 (6H, m), 7.03-7.18 (4H, m).

REFERENCE EXAMPLE 146 2-Hydroxy-4,6-dimethylbenzaldehyde

A mixed solution of 3,5-dimethylphenol (20.0 g, 164 mmol),paraformaldehyde (14.8 g, 492 mmol), magnesium chloride (23.4 g, 246mmol) and triethylamine (80 mL, 573 mmol) in acetonitrile (500 mL) washeated under reflux for 4 hours. The reaction solution was acidifiedwith hydrochloric acid, which was extracted with diethyl ether.

The organic layer was washed with a saturated sodium hydrogen carbonatesolution and a saturated brine, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:9) to obtain 20.8 g (yield 84%) of the title compound.Melting point: 48-49° C. (hexane).

¹H-NMR (CDCl₃) δ: 2.31 (3H, s), 2.55 (3H, s), 6.53 (1H, s), 6.62 (1H,s), 10.23 (1H, s), 11.95 (1H, s).

REFERENCE EXAMPLE 1472-(Hydroxy(4-isopropylphenyl)methyl)-3,5-dimethylphenol

To a solution of 1-bromo-4-isopropylbenzene (3.32 g, 16.7 mmol) in THF(30 mL) was added dropwise n-butyllithium (a 1.59 M hexane solution, 9.2mL, 14.7 mmol) under argon atmosphere at −78° C. The reaction solutionwas stirred for 30 minutes, a solution of2-hydroxy-4,6-dimethylbenzaldehyde obtained in Reference Example 146(1.0 g, 6.7 mmol) in THF (10 mL) was added dropwise thereto at −78° C.,and the mixture then was stirred for 30 minutes. The reaction solutionwas warmed to room temperature, water was added thereto to separate theorganic layer, and the aqueous layer was extracted with ethyl acetate.The combined organic layer was washed with a saturated brine, dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:2) to obtain 1.64 g (yield 91%)of the title compound. Melting point: 103-104° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.13 (3H, s), 2.26 (3H, s),2.77 (1H, d, J=2.4 Hz), 2.88 (1H, septet, J=6.9 Hz), 6.14 (1H, d, J=2.4Hz), 6.50 (1H, s), 6.62 (1H, s), 7.17 (2H, d, J=8.1 Hz), 7.28 (2H, d,J=8.1 Hz), 8.56 (1H, s).

REFERENCE EXAMPLE 148 2-(4-Isopropylbenzyl)-3,5-dimethylphenol

A mixture of 2-(hydroxy(4-isopropylphenyl)methyl)-3,5-dimethylphenolobtained in Reference Example 147 (12.3 g, 45.5 mmol) and 10%-palladiumcarbon (50% hydrous, 1.23 g) in acetic acid (90 mL) was heated underhydrogen atmosphere at 90° C. for 16 hours. The catalyst was removed,and the reaction solution was concentrated under reduced pressure.

The obtained residue was dissolved in ethyl acetate, washed with 1 Naqueous sodium hydroxide solution and a saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:3)to obtain 10.5 g (yield 90%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.24 (3H, s), 2.25 (3H, s),2.84 (1H, septet, J=6.9 Hz), 3.97 (2H, s), 4.58 (1H, s), 6.50 (1H, s),6.62 (1H, s), 7.05-7.12 (4H, m).

REFERENCE EXAMPLE 149 2-Bromo-3,5-dimethylphenol

To a solution of 3,5-dimethylphenol (15.0 g, 123 mmol) in carbondisulfide (330 mL) was slowly added N-bromosuccinimide (21.9 g, 123mmol) in several batches with ice-cooling, and the mixture was stirredat room temperature for 1 hour. The solvent was distilled off underreduced pressure, and the precipitated crystals were filtered and thenwere washed with ethyl acetate-hexane (10:1). The solution wasconcentrated, and the residue was purified by silica gel chromatography(ethyl-acetate:hexane=1:9) to obtain 16.3 g (yield 66%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 2.24 (3H, s), 2.34 (3H, s), 5.52 (1H, s), 6.62 (1H,s), 6.68 (1H, s).

REFERENCE EXAMPLE 150 2-Bromo-6-(4-isopropylbenzyl)-3,5-dimethylphenol

Using 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in ReferenceExample 148, the title compound was synthesized in the same manner as inReference Example 149.

Yield 75%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 2.20 (3H, s), 2.34 (3H, s),2.85 (1H, septet, J=6.9 Hz), 4.04 (2H, s), 5.66 (1H, s), 6.68 (1H, s),7.09 (4H, s).

REFERENCE EXAMPLE 151 2-Bromo-5-isopropylphenol2-Bromo-3-isopropylphenol

To a solution of 3-isopropylphenol (10.0 g, 73.4 mmol) in carbondisulfide (200 mL) was slowly added N-bromosuccinimide (13.1 g, 73.4mmol) with ice-cooling, and the mixture was stirred for 1 hour. Thereaction solution was stirred at room temperature for 1 hour, and thenwater was added thereto, which was extracted with ethyl acetate.

The combined organic layer was washed with water and a saturated brine,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=15:85) to obtain a mixture of2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol

(3:1) 11.0 g (yield 70%).

REFERENCE EXAMPLE 152 1-Bromo-4-isopropyl-2-methoxybenzene2-Bromo-1-isopropyl-3-methoxybenzene

A mixed solution of the mixture of 2-bromo-5-isopropylphenol obtained inReference Example 151 and 2-bromo-3-isopropylphenol (10.0 g, 51.3 mmol),methyl iodide (7.28 g, 51.3 mmol) and potassium carbonate (7.08 g, 51.3mmol) in acetone (200 mL) was heated under reflux under argon atmospherefor 8 hours. Water was added to the reaction solution, which wasextracted with ethyl acetate.

The combined organic layer was washed with a saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressureto obtain a mixture of 1-bromo-4-isopropyl-2-methoxybenzene and2-bromo-1-isopropyl-3-methoxybenzene 9.81 g (yield 83%).

REFERENCE EXAMPLE 153 Ethyl2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoate

A solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained inReference Example 148 (5.0 g, 19.7 mmol), 2-bromo isobutyric acid ethyl(11.5 g, 59.0 mmol) and potassium carbonate (8.13 g, 59.0 mmol) indimethylsulfoxide (20 mL) was stirred at 50° C. for 40 hours under argonatmosphere. Water was added to the reaction solution, which wasextracted with ethyl acetate. The combined organic layer was washed witha saturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain6.64 g (yield 92%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.18-1.28 (9H, m), 1.47 (6H, s), 2.19 (3H, s), 2.22(3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.97 (2H, s), 4.23 (2H, q, J=6.9Hz), 6.33 (1H, s), 6.61 (1H, s), 7.07 (4H, s).

REFERENCE EXAMPLE 154 Ethyl(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate

Using 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in ReferenceExample 148 and ethyl bromoacetate, the title compound was synthesizedin the same manner as in Reference Example 153. Yield 95%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.27 (3H, t, J=7.5 Hz), 2.22(3H, s), 2.27 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 4.04 (2H, s), 4.24(2H, q, J=7.5 Hz), 4.58 (2H, s), 6.46 (1H, s), 6.66 (1H, s), 7.03-7.13(4H, m).

REFERENCE EXAMPLE 155 Ethyl (2,3,5-trimethylphenoxy)acetate

Using 2,3,5-trimethylphenol and ethyl bromoacetate, the title compoundwas synthesized in the same manner as in Reference Example 153. Yield:quantitative. Oily matter.

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.5 Hz), 2.17 (3H, s), 2.23 (3H, s),2.36 (3H, s), 4.26 (2H, q, J=7.5 Hz), 4.60 (2H, s), 6.42 (1H, s), 6.65(1H, s).

REFERENCE EXAMPLE 1562-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic acid

A mixed solution of ethyl2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoateobtained in Reference Example 153 (6.65 g, 18.1 mmol) and a 8 N aqueoussodium hydroxide solution (4.5 mL) in methanol (40 mL)-THF (20 mL) wasstirred at room temperature for 16 hours. The reaction solution wasacidified with hydrochloric acid, and the aqueous layer was extractedwith ethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, filtered, and then concentrated under reduced pressure toobtain 5.59 g (yield 91%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.49 (6H, s), 2.22 (3H, s),2.26 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.97 (2H, s), 6.50 (1H, s),6.71 (1H, s), 7.01 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz), 1Hunidentified.

REFERENCE EXAMPLE 157 (2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)aceticacid

Using ethyl (2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetate obtainedin Reference Example 154, the title compound was synthesized in the samemanner as in Reference Example 156. Yield 75%. Melting point: 104-105°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.26 (3H, s), 2.30 (3H, s),2.84 (1H, septet, J=6.9 Hz), 4.02 (2H, s), 4.57 (2H, s), 6.48 (1H, s),6.73 (1H, s), 7.04 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz), 1Hunidentified.

REFERENCE EXAMPLE 158 (2,3,5-Trimethylphenoxy)acetic acid

Using ethyl (2,3,5-dimethylphenoxy)acetate obtained in Reference Example155, the title compound was synthesized in the same manner as inReference Example 156. Yield 92%. Melting point: 129-130° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 2.16 (3H, s), 2.24 (3H, s), 2.27 (3H, s), 4.67 (2H,s), 6.44 (1H, s), 6.68 (1H, s), 1H unidentified

REFERENCE EXAMPLE 1591-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)acetone

A mixed solution of 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained inReference Example 148 (1.0 g, 3.93 mmol), potassium carbonate (1.30 g,9.44 mmol), chloroacetone (436 mg, 4.72 mmol) and potassium iodide (100mg) in acetone (15 mL) was heated under reflux for 16 hours. Water wasadded to the reaction solution, which was extracted with ethyl acetate.The combined organic layer was washed with a saturated brine, dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure, and the obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to obtain 888 mg (yield 73%)of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.10 (3H, s), 2.24 (3H, s),2.28 (3H, s), 2.80-2.90 (1H, septet, J=6.9 Hz), 4.04 (2H, s), 4.42 (2H,s), 6.40 (1H, s), 6.68 (1H, s), 7.02 (2H, d, J=8.1 Hz), 7.07 (2H, d,J=8.1 Hz).

REFERENCE EXAMPLE 160)1-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)butan-2-one

Using 2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in ReferenceExample 148 and 1-bromobutan-2-one, the title compound was synthesizedin the same manner as in Reference Example 159. Yield 88%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.97 (3H, t, J=7.2 Hz), 1.20 (6H, d, J=6.9 Hz), 2.45(3H, s), 2.88 (3H, s), 2.42 (2H, q, J=7.2 Hz), 2.84 (1H, septet, J=6.9Hz), 4.05 (2H, s), 4.45 (2H, s), 6.42 (1H, s), 6.69 (1H, s), 7.04 (2H,d, J=8.1 Hz), 7.08 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 1611-(3-Bromophenyl)-2-(2,3,5-trimethylphenoxy)ethanone

Using 2,3,5-trimethylphenol and 2-bromo-1-(3-bromophenyl)ethanone, thetitle compound was synthesized in the same manner as in ReferenceExample 159. Yield 52%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.16 (3H, s), 2.24 (3H, s), 2.26 (3H, s), 5.16 (2H,s), 6.46 (1H, s), 6.66 (1H, s), 7.37 (1H, t, J=8.0 Hz), 7.70-7.76 (1H,m), 7.91-7.96 (1H, m), 8.15-8.17 (1H, m).

REFERENCE EXAMPLE 1621-(3-Methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone

Using 2,3,5-trimethylphenol and 2-bromo-1-(3-methoxyphenyl)ethanone, thetitle compound was synthesized in the same manner as in ReferenceExample 159. Yield 88%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.18 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 3.86 (3H,s), 5.22 (2H, s), 6.46 (1H, s), 6.65 (1H, s), 7.13-7.20 (1H, m), 7.40(1H, t, J=7.5 Hz), 7.53-7.61 (2H, m).

REFERENCE EXAMPLE 1631-(4-Methylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone

Using 2,3,5-trimethylphenol and 2-bromo-1-(4-methylphenyl)ethanone, thetitle compound was synthesized in the same manner as in ReferenceExample 159. Yield 75%. Melting point: 94-95° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.17 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 2.42 (3H,s), 5.18 (2H, s), 6.45 (1H, s), 6.63 (1H, s), 7.27 (2H, d, J=8.1 Hz),7.91 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 164 2-Bromo-1-(4-isopropylphenyl)ethanone

To a solution of cumene (42 g, 350 mmol) and aluminum chloride (56.0 g,420 mmol) in dichloromethane (500 mL) was added bromoacetylbromide (33.5mL, 385 mmol) at −40° C. for 40 minutes, and the mixture was stirreduntil it was warmed to −10° C. for 2 hours. The reaction solution waspoured into ice-cold water to separate the organic layer. The organiclayer was washed with a saturated sodium hydrogen carbonate solution anda saturated brine, and then was dried over sodium sulfate. The solventwas distilled off under reduced pressure to obtain 84 g (yield 99%) ofthe title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 2.98 (1H, septet, J=6.9 Hz),4.44 (2H, s), 7.34 (2H, d, J=8.4 Hz), 7.92 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 1654-Bromo-1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)ethanone

Using 2,3,5-trimethylphenol, 4-bromo-2,3,5-trimethylphenol wassynthesized in the same manner as in Reference Example 23. Using thiscompound and 2-bromo-1-(4-isopropylphenyl)ethanone obtained in ReferenceExample 164, the title compound was synthesized in the same manner as inReference Example 159. Yield 51%. Melting point: 71-72° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.6 Hz), 2.28 (3H, s), 2.35 (3H, s),2.40 (3H, s), 2.98 (1H, septet, J=6.6 Hz), 5.23 (2H, s), 6.55 (1H, s),7.35 (2H, d, J=8.1 Hz), 7.94 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 1661-((2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridine

To a solution of (2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acidobtained in Reference Example 157 (9.00 g, 28.8 mmol) in THF (90 mL) wasadded dropwise oxalylchloride (3.77 mL, 43.2 mmol) with ice-cooling, andwas then added DMF (four drops), and then the mixture was stirred for 30minutes. The reaction solution was stirred at room temperature for 30minutes, and the solvent was distilled off under reduced pressure. To asolution of propyleneimine (1.97 g, 34.6 mmol) and triethylamine (4.82mL, 34.6 mmol) in THF (80 mL) was added dropwise the obtained solutionof acid chloride in THF (100 mL) with ice-cooling. The mixture wasstirred for 30 minutes, and then was warmed to room temperature, andwater was added to the reaction solution, which was extracted with ethylacetate. The combined organic layer was washed with a saturated brine,dried over sodium sulfate, and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=2:3) to obtain 10.0 g (yield 99%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.15 (3H, d, J=5.7 Hz), 1.20 (6H, d, J=6.9 Hz), 1.86(1H, d, J=3.6 Hz), 2.23 (3H, s), 2.26-2.30 (4H, m), 2.40-2.50 (1H, m),2.84 (1H, septet, J=6.9 Hz), 4.05 (2H, s), 4.56 (1H, d, J=15.6 Hz), 4.63(1H, d, J=15.6 Hz), 6.53 (1H, s), 6.69 (1H, s), 7.05-7.10 (4H, m).

REFERENCE EXAMPLE 167 (2,3,5-Trimethylphenoxy)acetyl)-2-methylaziridine

Using (2,3,5-trimethylphenoxy)acetic acid obtained in Reference Example158, the title compound was obtained in the same manner as in ReferenceExample 166. Yield 77%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.32 (3H, d, J=5.4 Hz), 2.03-2.05 (1H, m), 2.18 (3H,s), 2.24 (3H, s), 2.26 (3H, s), 2.45 (1H, d, J=5.4 Hz), 2.60-2.69 (1H,m), 4.63 (2H, s), 6.46 (1H, s), 6.65 (1H, s).

REFERENCE EXAMPLE 1681-(5-Methylpyridine-2-yl)-2-(2,3,5-trimethylphenoxy)ethanone

To a solution of 2-bromo-5-methylpyridine (958 mg, 5.57 mmol) in THF (3mL)-ether (10 ml) was added dropwise n-butyllithium (a 1.56 M hexanesolution, 3.9 mL, 6.13 mmol) at −78° C. under argon atmosphere. Thereaction solution was stirred for 30 minutes, to which a solution of(2,3,5-trimethylphenoxy)acetyl)-2-methylaziridine obtained in ReferenceExample 167 (1.43 g, 6.13 mmol) in THF (5 ml) was added dropwise at thesame temperature. The reaction solution was warmed to room temperature,ice was added thereto, which was extracted with ethyl acetate. Thecombined organic layer was washed with a saturated brine, dried oversodium sulfate, and then concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate:hexane 1:4) to obtain 795 mg (yield 53%) of the title compound.Melting point: 94-95° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.25 (9H, s), 2.45 (3H, s), 5.60 (2H, s), 6.52 (1H,s), 6.64 (1H, s), 7.65-7.70 (1H, m), 8.00 (1H, d, J=7.8 Hz), 8.49-8.51(1H, m).

REFERENCE EXAMPLE 1691-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy)pentan-2-one

To a solution of1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridineobtained in Reference Example 166 (1.0 g, 2.85 mmol) in THF (20 mL) wasadded dropwise n-propylmagnesium bromide (a 2.0 M THF solution, 1.43 mL,2.85 mmol) under argon atmosphere with ice-cooling, and the mixture wasstirred for 30 minutes. The reaction solution was warmed to roomtemperature, water was added thereto, which was extracted with ethylacetate.

The organic layer was dried over anhydrous sodium sulfate, and then wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain920 mg (yield 95%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 0.83 (3H, t, J=7.5 Hz), 1.20 (6H, d, J=6.9 Hz),1.40-1.59 (2H, m), 2.25 (3H, s), 2.29 (3H, s), 2.39 (2H, t, J=7.5 Hz),2.84 (1H, septet, J=6.9 Hz), 4.05 (2H, s), 4.43 (2H, s), 6.41 (1H, s),6.69 (1H, s), 7.03 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 1701-(2-(4-Isopropylbenzyl)-3,5-dimethylphenoxy-3-methylbutan-2-one

Using1-((2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetyl)-2-methylaziridineobtained in Reference Example 166 and isopropylmagnesium bromide, thetitle compound was synthesized in the same manner as in ReferenceExample 169. Yield 24%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.98 (6H, d, J=7.8 Hz), 1.20 (6H, d, J=6.9 Hz), 2.25(3H, s), 2.29 (3H, s), 2.75-2.89 (2H, m), 4.05 (2H, s), 4.51 (2H, s),6.42 (1H, s), 6.69 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.08 (2H, d, J=8.1Hz).

REFERENCE EXAMPLE 1711-(2-Isopropyl-6-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone1-(4-Isopropyl-2-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone

To a solution of the mixture of 1-bromo-4-isopropyl-2-methoxybenzene and2-bromo-1-isopropyl-3-methoxybenzene obtained in Reference Example 152(5.73 g, 25.0 mmol) in THF (100 mL) was added dropwise n-butyllithium (a1.60 M hexane solution, 17.2 mL, 27.5 mmol) under argon atmosphere at−70° C. The reaction solution was stirred for 30 minutes, and then towhich a solution of the2-methyl-1-((2,3,5-(trimethylphenoxy)acetyl)aziridine obtained inReference Example 167 (5.84 g, 25.0 mmol) in THF (20 mL) was addeddropwise, and the mixture was stirred at −70° C. for 30 minutes, andthen was warmed to room temperature. Water was added to the reactionsolution, which was extracted with ethyl acetate, and the organic layerwas dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to obtain 6.27 g (yield 77%)of a mixture of the title compounds.

REFERENCE EXAMPLE 172 4-Hydroxy-2-methyl-1-naphthyl acetate

To a solution of 4-(acetyloxy)-2-methyl-1-naphthyl acetate (25 g, 96.8mmol) in methanol (300 mL) was added potassium carbonate (58.1 g, 420mmol), and the mixture was stirred under argon atmosphere at roomtemperature for 15 minutes. Water was poured into the mixture, which wasneutralized with hydrochloric acid and then extracted with ethylacetate. The extract was washed with a saturated brine and dried oversodium sulfate, and the solvent was distilled off under reduced pressureto obtain 21 g (yield: quantitative) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.48 (3H, s), 5.90 (1H, br s), 6.43 (1H,s), 7.34-7.51 (2H, m), 7.63 (1H, d, J=8.4 Hz), 8.00 (1H, d, J=9.6 Hz).

REFERENCE EXAMPLE 173 3-Methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate

To a suspension of sodium hydride (a 60% liquid paraffin dispersion, 1.8g, 40 mmol) in DMF (60 mL) was added triethyl3-methyl-4-phosphonocrotonate (11 g, 41.6 mmol) at 0° C., and themixture was stirred at room temperature for 1 hour. To the reactionsolution was added cyclohexanone (3.93 g, 40 mmol), and the mixture wasstirred for 3 hours. Water was added to the reaction solution and theproduct was extracted with diisopropyl ether. The combined extract waswashed with water, dried over magnesium sulfate, and then concentratedunder reduced pressure to obtain oily crude resultant product of ethyl4-cyclohexylidene-3-methyl-2-butenoate. To a mixed solution of thiscompound in THF (160 mL) and methanol (40 mL) was added a 12 N aqueoussodium hydroxide solution (4.0 mL) at room temperature, and the mixturewas stirred for 16 hours, and then was concentrated under reducedpressure. To the residue was added water and hydrochloric acid, and themixture was acidified, which was extracted with ethyl acetate. Theorganic layer was washed with water, and then was dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain the crude resultant product of4-cyclohexylidene-3-methyl-2-butenoic acid. To a mixture of thiscompound (6.1 g, 33.8 mmol) in acetic acid (150 mL) was added sodiumacetate (12 g, 33.8 mmol) at room temperature, and the mixture washeated under reflux under argon atmosphere for 24 hours. The solvent wasconcentrated under reduced pressure, water was added to the residue,which was extracted with ethyl acetate, and the organic layer was washedwith a saturated sodium hydrogen carbonate solution and water, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:10) to obtain 5.1 g (yield 63%)of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.68-1.87 (4H, m), 2.27 (3H, s), 2.29 (3H, s),2.44-2.58 (2H, m), 2.68-2.79 (2H, m), 6.64 (1H, s), 6.78 (1H, s).

REFERENCE EXAMPLE 174 6-Methyl-2,3-dihydro-1H-inden-4-yl acetate

Using cyclopentanone, the title compound was synthesized in the samemanner as in Reference Example 173.

Yield 21%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.00-2.14 (2H, m), 2.28 (3H, s), 2.31 (3H, s), 2.73(2H, t, J=7.5 Hz), 2.90 (2H, t, J=7.5 Hz), 6.65 (1H, s), 6.91 (1H, s).

REFERENCE EXAMPLE 175 3-Methyl-5,6,7,8-tetrahydro-1-naphtalenol

To a mixed solution of 3-methyl-5,6,7,8-tetrahydro-1-naphthalenylacetate synthesized in Reference Example 173 (5.1 g, 25.1 mmol) in THF(120 mL) and methanol (30 mL) was added 12 N aqueous sodium hydroxidesolution (2.5 mL) at room temperature, and the mixture was stirred for30 minutes, and then concentrated under reduced pressure. Water andhydrochloric acid were added to the residue, and the mixture wasacidified, which was extracted with ethyl acetate. The organic layer waswashed with water and a saturated brine, and then was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the obtained residue was crystallized with ethylacetate-hexane to obtain 4.1 g (yield 99%) of the title compound.Melting point: 95-96° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.68-1.87 (4H, m), 2.23 (3H, s), 2.58 (2H, t, J=6.0Hz), 2.70 (2H, t, J=6.0 Hz), 4.67 (1H, br s), 6.42 (1H, s), 6.50 (1H,s).

REFERENCE EXAMPLE 176 6-Methyl-4-indanol

Using 6-methyl-2,3-dihydro-1H-inden-4-yl acetate synthesized inReference Example 174, the title compound was synthesized in the samemanner as in Reference Example 175. Yield 81%. Melting point: 82-83° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 2.02-2.14 (2H, m), 2.27 (3H, s), 2.80 (2H, t, J=7.5Hz), 2.87 (2H, t, J=7.5 Hz), 4.62 (1H, br s), 6.43 (1H, s), 6.65 (1H,s).

REFERENCE EXAMPLE 1772-(3,4,5-Trimethylphenoxy)-1-(4-isopropylphenyl)ethanone

2-Bromo-1-(4-isopropylphenyl)ethanone obtained in Reference Example 164(20 g, 82.9 mmol) and 3,4,5-trimethylphenol (10.3 g, 75.4 mmol) wereadded to a solution of potassium carbonate (12.5 g, 90.5 mmol) inacetonitrile solution (200 mL), and mixture was stirred with heatingunder reflux for 6 hours. The reaction solution was ice-cooled, waspoured into cold water, which was extracted with ethyl acetate. Theextract was washed with a saturated brine, and then was dried oversodium sulfate. Then, the solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:10). The obtained oily matter wascrystallized from hexane-ethyl acetate to obtain 21.5 g (yield 96%) ofthe title compound. Melting point: 96-98° C.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 2.09 (3H, s), 2.23 (6H, s),2.97 (1H, septet, J=6.9 Hz), 5.19 (2H, s), 6.61 (2H, s), 7.33 (2H, d,J=8.4 Hz), 7.93 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 1784-(2-(4-Isopropylphenyl)-2-oxoethoxy)-2-methyl-1-naphthyl acetate

Using 4-hydroxy-2-methyl-1-naphthyl acetate synthesized in ReferenceExample 172, the title compound was synthesized in the same manner as inReference Example 177. Yield 65%. Melting point: 105-106° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 2.27 (3H, s), 2.45 (3H, s),2.98 (1H, septet, J=6.9 Hz), 5.36 (2H, s), 6.60 (1H, s), 7.35 (2H, d,J=8.1 Hz), 7.40-7.56 (2H, m), 7.66 (1H, d, J=8.7 Hz), 7.99 (2H, d, J=8.1Hz), 8.30 (1H, d, J=8.7 Hz).

REFERENCE EXAMPLE 1791-(4-Isopropylphenyl)-2-((3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy)ethanone

Using 3-methyl-5,6,7,8-tetrahydro-1-naphtalenol synthesized in ReferenceExample 175, the title compound was synthesized in the same manner as inReference Example 177. Yield 65%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 1.65-1.82 (4H, m), 2.25 (3H,s), 2.62-2.75 (4H, m), 2.98 (1H, septet, J=6.9 Hz), 5.20 (2H, s), 6.39(1H, s), 6.55 (1H, s), 7.33 (2H, d, J=8.1 Hz), 7.95 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 1801-(4-Isopropylphenyl)-2-((6-methyl-2,3-dihydro-1H-inden-4-yl)oxy)ethanone

Using 6-methyl-4-indanol synthesized in Reference Example 176, the titlecompound was synthesized in the same manner as in Reference Example 177.Yield 91%. Melting point: 68-69° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.28 (6H, d, J=6.9 Hz), 1.65-1.82 (2H, quintet, J=7.5Hz), 2.27 (3H, s), 2.82-3.05 (5H, m), 5.22 (2H, s), 6.38 (1H, s), 6.70(1H, s), 7.34 (2H, d, J=8.4 Hz), 7.96 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 1812-((3,5-Dimethylphenyl)thio)-1-(4-isopropylphenyl)ethanone

Using 3,5-dimethylthiophenol, the title compound was synthesized in thesame manner as in Reference Example 177.

Yield 81%. Melting point: 46-47° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 2.26 (6H, s), 2.97 (1H,septet, J=6.9 Hz), 4.24 (2H, s), 6.85 (1H, s), 7.01 (2H, s), 7.31 (2H,d, J=8.1 Hz), 7.88 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 182 7-(4-Isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran

Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone obtained inReference Example 159, the title compound was obtained in the samemanner as in Reference 143. Yield 76%. Melting point: 106-107° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 2.30 (3H, s), 2.36 (3H, s),2.58 (3H, s), 2.80-2.90 (1H, septet, J=6.9 Hz), 4.19 (2H, s), 6.79 (1H,s), 7.07 (4H, s), 7.29 (1H, s).

REFERENCE EXAMPLE 1833-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-1-benzofuran

Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)butan-2-one obtainedin Reference Example 160, the title compound was obtained in the samemanner as in Reference Example 143. Yield 98%. Melting point: 62-64° C.(diisopropyl ether-methanol).

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.6 Hz), 1.31 (3H, t, J=7.6 Hz), 2.31(3H, s), 2.76 (3H, s), 2.77-2.89 (3H, m), 4.19 (2H, s), 6.79 (1H, s),7.07 (4H, s), 7.29 (1H, s).

REFERENCE EXAMPLE 1847-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran

Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)pentan-2-one obtainedin Reference Example 169, the title compound was obtained in the samemanner as in Reference Example 143. Yield 92%. Melting point: 89-90° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.03 (3H, t, J=7.5 Hz), 1.19 (6H, d, J=6.9 Hz), 1.70(2H, m), 2.31 (3H, s), 2.57 (3H, s), 2.74 (2H, t, J=7.5 Hz), 2.83 (1H,septet, J=6.9 Hz), 4.20 (2H, s), 6.80 (1H, s), 7.08 (4H, s), 7.30 (1H,s).

REFERENCE EXAMPLE 1853-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-1-benzofuran

Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy-3-methylbutan-2-oneobtained in Reference Example 170, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 87%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 1.33 (6H, d, J=6.9 Hz), 2.32(3H, s), 2.59 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.28 (1H, septet,J=6.9 Hz), 4.20 (2H, s), 6.81 (1H, s), 7.08 (4H, s), 7.30 (1H, s).

REFERENCE EXAMPLE 186 3-(3-Bromophenyl)-4,6,7-trimethyl-1-benzofuran

Using 1-(3-bromophenyl)-2-(2,3,5-trimethylphenoxy)ethanone obtained inReference Example 161, the title compound was synthesized in the samemanner as in Reference Example 143. Yield 82%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 6.84 (1H,s), 7.28 (1H, t, J=8.1 Hz), 7.35-7.39 (1H, m), 7.48-7.53 (2H, m),7.59-7.60 (1H, m).

REFERENCE EXAMPLE 187 3-(3-Methoxyphenyl)-4,6,7-trimethyl-1-benzofuran

Using 1-(3-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone obtained inReference Example 162, the title compound was synthesized in the samemanner as in Reference Example 143. Yield 82%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 3.83 (3H,s), 6.84 (1H, s), 6.90-7.04 (3H, m), 7.32 (1H, t, J=7.5 Hz), 7.51 (1H,s).

REFERENCE EXAMPLE 1883-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-1-benzofuran

A mixed solution of the mixture of1-(2-isopropyl-6-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanone and1-(4-isopropyl-2-methoxyphenyl)-2-(2,3,5-trimethylphenoxy)ethanoneobtained in Reference Example 171 (6.27 g, 19.2 mmol) andMontmorillonite KSF (9.40 g) in toluene (100 mL) was stirred under argonatmosphere at 90° C. for 5 hours. The reaction solution was filteredthrough celite, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (ethylacetate hexane=15:85) to obtain 2.34 g (yield 40%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 2.10 (3H, s), 2.34 (3H, s),2.41 (3H, s), 3.00 (1H, septet, J=6.9 Hz), 3.76 (3H, s), 6.77-6.80 (2H,m), 6.83-6.86 (1H, m), 7.17 (1H, d, J=7.8 Hz), 7.44 (1H, s).

REFERENCE EXAMPLE 1891-(4-Bromo-2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone

Using 1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetone obtained inReference Example 159, the title compound was synthesized in the samemanner as in Reference Example 23. Yield 73%. Melting point: 93-94° C.(methanol-THF).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.12 (3H, s), 2.39 (6H, s),2.84 (1H, septet, J=6.9 Hz), 4.13 (2H, s), 4.44 (2H, s), 6.51 (1H, s),7.00 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 1905-Bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran

Using 1-(4-bromo-1-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)acetoneobtained in Reference Example 189, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 84%. Melting point:76-77° C. (methanol-THF).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.37 (3H, s), 2.44 (3H, s),2.71 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 4.28 (2H, s), 7.04 (2H, d,J=8.7 Hz), 7.08 (2H, d, J=8.7 Hz), 7.32 (1H, s).

REFERENCE EXAMPLE 191 4,6,7-Trimethyl-3-(4-methylphenyl)-1-benzofuran

A mixture of 1-(4-methylphenyl)-2-(2,3,5-trimethylphenoxy)ethanoneobtained in Reference Example 163 (1.0 g, 3.73 mmol) and polyphosphoricacid (6.0 g) was stirred at 80° C. for one and half hours. Water wasadded to the reaction solution, which was extracted with ethyl acetate.The organic layer was washed with a saturated sodium hydrogen carbonatesolution, dried over anhydrous sodium sulfate, and then concentratedunder reduced pressure to obtain 770 mg (yield 83%) of the titlecompound. Melting point: 112-113° C. (ethyl acetate-methanol).

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.35 (3H, s), 2.41 (3H, s), 2.42 (3H,s), 6.81 (1H, s), 7.20 (2H, d, J=7.8 Hz), 7.31 (2H, d, J=7.8 Hz), 7.46(1H, s).

REFERENCE EXAMPLE 1925-Methyl-2-(4,6,7-trimethyl-1-benzofuran-3-yl)pyridine

Using 1-(5-methylpyridin-2-yl)-2-(2,3,5-trimethylphenoxy)ethanoneobtained in Reference Example 168, the title compound was synthesized inthe same manner as in Reference Example 191. Yield 87%. Melting point:134-135° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 2.30 (3H, s), 2.36 (3H, s), 2.39 (3H, s), 2.42 (3H,s), 6.85 (1H, s), 7.37 (1H, d, J=8.1 Hz), 7.53 (1H, dd, J=2.1, 8.1 Hz),7.67 (1H, s), 8.54 (1H, d, J=2.1 Hz).

REFERENCE EXAMPLE 1935-Bromo-3-(4-isopropyl)-4,6,7-trimethyl-1-benzofuran

Using 4-bromo-1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)ethanoneobtained in Reference Example 165, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 86%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=7.0 Hz), 2.30 (3H, s), 2.51 (6H, s),2.97 (1H, septet, J=7.0 Hz), 7.24-7.35 (4H, m), 7.48 (1H, s).

REFERENCE EXAMPLE 194)3-(4-Isopropylphenyl)-4,5,6-trimethyl-1-benzofuran

Using 2-(3,4,5-trimethylphenoxy)-1-(4-isopropylphenyl)ethanone obtainedin Reference Example 177, the title compound was synthesized in the samemanner as in Reference Example 143. Yield 96%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.18 (3H, s), 2.21 (3H, s),2.39 (3H, s), 2.96 (1H, septet, J=6.9 Hz), 7.19 (1H, s), 7.25 (2H, d,J=8.1 Hz), 7.33 (2H, d, J=8.1 Hz), 7.39 (1H, s).

REFERENCE EXAMPLE 1953-(4-Isopropylphenyl)-4-methylnaphtho[1,2-b]furan-5-yl acetate

Using 4-(2-(4-isopropylphenyl)-2-oxoethoxy)-2-methyl-1-naphthyl acetateobtained in Reference Example 178, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 88%. Melting point:118-119° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=6.9 Hz), 2.15 (3H, s), 2.47 (3H, s),2.98 (1H, septet, J=6.9 Hz), 7.28 (2H, d, J=8.4 Hz), 7.39 (2H, d, J=8.4Hz), 7.47-7.59 (2H, m), 7.67 (1H, s), 7.77 (1H, d, J=8.7 Hz), 8.31 (1H,d, J=8.7 Hz).

REFERENCE EXAMPLE 1963-(4-Isopropylphenyl)-4-methyl-6,7,8,9-tetrahydronaphtho[1,2-b]furan

Using1-(4-isopropylphenyl)-2-((3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl)oxy)ethanoneobtained in Reference Example 179, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 56%. Melting point:97-98° C.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 1.75-1.98 (4H, m), 2.20 (3H,s), 2.75-3.02 (5H, m), 6.74 (1H, s), 7.26 (2H, d, J=8.1 Hz), 7.35 (2H,d, J=8.1 Hz), 7.48 (1H, s).

REFERENCE EXAMPLE 1973-(4-Isopropylphenyl)-4-methyl-7,8-dihydro-6H-indeno[4,5-b]furan

Using1-(4-isopropylphenyl)-2-((6-methyl-2,3-dihydro-1H-inden-4-yl)oxy)ethanoneobtained in Reference Example 180, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 77%. Melting point:70-72° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.11-2.24 (5H, m), 2.90-3.06(3H, m), 3.13 (2H, t, J=7.5 Hz), 6.91 (1H, s), 7.24 (2H, d, J=8.1 Hz),7.34 (2H, d, J=8.1 Hz), 7.46 (1H, s).

REFERENCE EXAMPLE 1983-(4-Isopropylphenyl)-4,6-dimethyl-1-benzothiophene

Using 2-((3,5-(dimethylphenyl)thio)-1-(4-isopropylphenyl)ethanoneobtained in Reference Example 181, the title compound was synthesized inthe same manner as in Reference Example 143. Yield 86%. Melting point:83-84° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.06 (3H, s), 2.43 (3H, s),2.97 (1H, septet, J=6.9 Hz), 6.91 (1H, s), 7.10 (1H, s), 7.22 (2H, d,J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.53 (1H, s).

REFERENCE EXAMPLE 1993-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

To a mixed solution of3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuranobtained in Reference Example 183 (941 mg, 2.94 mmol) in trifluoroaceticacid (5 mL) was added dropwise triethylsilane (0.94 mL, 5.87 mmol), andthe mixture was stirred at room temperature for 1 hour. Water was addedto the reaction solution, which was extracted with ethyl acetate, andthen the organic layer was washed with a saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain940 mg (yield 99%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 0.95 (3H, t, J=7.6 Hz), 1.19 (6H, d, J=6.9 Hz),1.48-1.64 (2H, m), 2.16 (3H, s), 2.24 (3H, s), 2.83 (1H, septet, J=6.9Hz), 3.30-3.36 (1H, m), 3.90 (2H, s), 4.36 (1H, dd, J=3.6, 8.7 Hz), 4.50(1H, t, J=8.7 Hz), 4.52 (1H, s), 7.08 (4H, s).

REFERENCE EXAMPLE 2007-(4-Isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran

Using 7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran obtained inReference Example 182, the title compound was synthesized in the samemanner as in Reference Example 199. Yield: quantitative. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 2.16(3H, s), 2.24 (3H, s), 2.80-2.90 (1H, septet, J=6.9 Hz), 3.40-3.55 (1H,m), 3.90 (2H, s), 3.17 (1H, dd, J=4.2, 8.4 Hz), 4.56 (1H, t, J=4.2, 8.4Hz), 6.48 (1H, s), 7.07 (4H, s).

REFERENCE EXAMPLE 2017-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran

Using 7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-1-benzofuran obtainedin Reference Example 184, the title compound was synthesized in the samemanner as in Reference Example 199. Yield 99%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.5 Hz), 1.15 (6H, d, J=6.9 Hz), 1.37(2H, m), 1.47-1.69 (2H, m), 2.16 (3H, s), 2.24 (3H, s), 2.83 (1H,septet, J=6.9 Hz), 3.30-3.90 (1H, m), 3.89 (2H, s), 4.34 (1H, dd, J=3.3,8.7 Hz), 4.48 (1H, t, J=8.7 Hz), 6.48 (1H, s), 7.06 (4H, s).

REFERENCE EXAMPLE 2023-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using 3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-1-benzofuranobtained in Reference Example 185, the title compound was synthesized inthe same manner as in Reference Example 199. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.19(6H, d, J=6.9 Hz), 2.05-2.17 (1H, m), 2.15 (3H, s), 2.24 (3H, s), 2.83(1H, septet, J=6.9 Hz), 3.33-3.38 (1H, m), 3.84 (1H, d, J=15.6 Hz), 3.95(1H, d, J=15.6 Hz), 4.36 (1H, t, J=9.0 Hz), 4.50 (1H, dd, J=2.7, 9.0Hz), 6.49 (1H, s), 7.06 (4H, s)

REFERENCE EXAMPLE 2033-(3-Bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(3-bromophenyl)-4,6,7-trimethyl-1-benzofuran obtained inReference Example 186, the title compound was synthesized in the samemanner as in Reference Example 199.

Yield 82%. Melting point: 73-74° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 4.39 (1H,dd, J=4.8, 9.0 Hz), 4.50 (1H, dd, J=4.8, 9.0 Hz), 4.83 (1H, t, J=9.0Hz), 6.50 (1H, s), 7.06 (1H, d, J=7.5 Hz), 7.15 (1H, t, J=7.7 Hz), 7.30(1H, s), 7.35 (1H, d, J=7.7 Hz).

REFERENCE EXAMPLE 2043-(3-Methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(3-methoxyphenyl)-4,6,7-trimethyl-1-benzofuran obtained inReference Example 187, the title compound was synthesized in the samemanner as in Reference Example 199.

Yield 82%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.91 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.76 (3H,s), 4.42 (1H, dd, J=4.8, 8.7 Hz), 4.52 (1H, dd, J=4.8, 8.7 Hz), 4.84(1H, t, J=8.7 Hz), 6.48 (1H, s), 6.68-6.77 (3H, m), 7.20 (1H, t, J=7.8Hz).

REFERENCE EXAMPLE 2053-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-1-benzofuranobtained in Reference Example 188, the title compound was synthesized inthe same manner as in Reference Example 199. Yield 79%. Melting point:102-103° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.95 (3H, s), 2.14 (3H, s),2.24 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.87 (3H, s), 4.34 (1H, dd,J=3.3, 7.5 Hz), 4.78-4.88 (2H, m), 6.52 (1H, s), 6.66 (2H, s), 6.73 (1H,s).

REFERENCE EXAMPLE 2064,6,7-Trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran

Using 4,6,7-trimethyl-3-(4-methylphenyl)-1-benzofuran obtained inReference Example 191, the title compound was synthesized in the samemanner as in Reference Example 144.

Yield 81%. Melting point: 65-66° C. (THF-methanol).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.31 (3H,s), 4.39 (1H, dd, J=5.2, 8.8 Hz), 4.51 (1H, dd, J=5.2, 8.8 Hz), 4.84(1H, t, J=8.8 Hz), 6.48 (1H, s), 7.02 (2H, d, J=8.4 Hz), 7.09 (2H, d,J=8.4 Hz).

REFERENCE EXAMPLE 2075-Methyl-2-(4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridine

Using 5-methyl-2-(4,6,7-trimethyl-1-benzofuran-3-yl)pyridine obtained inReference Example 192, the title compound was synthesized in the samemanner as in Reference Example 144. Yield 89%. Melting point: 69-70° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.92 (3H, s), 2.14 (3H, s), 2.22 (3H, s), 2.29 (3H,s), 4.55 (1H, dd, J=4.5, 9.0 Hz), 4.72 (1H, dd, J=4.5, 9.0 Hz), 4.88(1H, t, J=9.0 Hz), 6.49 (1H, s), 6.89 (1H, d, J=7.8 Hz), 7.37 (1H, dd,J=2.1, 7.8 Hz), 8.37 (1H, d, J=2.1 Hz)

REFERENCE EXAMPLE 2083-(4-Isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-4,5,6-trimethyl-1-benzofuran obtained inReference Example 194, the title compound was synthesized in the samemanner as in Reference Example 199. Yield 74%. Melting point: 70-71° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s), 2.06 (3H, s),2.26 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.38 (1H, dd, J=8.7, 4.5 Hz),4.49 (1H, dd, J=9.0, 4.2 Hz), 4.78 (1H, t, J=8.7 Hz), 6.59 (1H, s), 7.03(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 2093-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ylacetate

Using 3-(4-isopropylphenyl)-4-methylnaphtho[1,2-b]furan-5-yl acetateobtained in Reference Example 195, the title compound was synthesized inthe same manner as in Reference Example 199. Yield 74%. Melting point:109-110° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s), 2.42 (3H, s),2.86 (1H, septet, J=6.9 Hz), 4.63 (1H, dd, J=8.7, 5.1 Hz), 4.74 (1H, dd,J=9.3, 5.1 Hz), 5.06 (1H, t, J=9.0 Hz), 7.05 (2H, d, J=8.4 Hz), 7.12(2H, d, J=8.4 Hz), 7.38-7.50 (2H, m), 7.66 (1H, d, J=8.7 Hz), 7.97 (1H,d, J=8.7 Hz).

REFERENCE EXAMPLE 2103-(4-Isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan

Using3-(4-isopropylphenyl)-4-methyl-6,7,8,9-tetrahydronaphtho[1,2-b]furanobtained in Reference Example 196, the title compound was synthesized inthe same manner as in Reference Example 199. Yield 80%. Melting point:54-55° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.70-1.98 (7H, m), 2.57-2.76(4H, m), 2.87 (1H, septet, J=6.9 Hz), 4.43 (1H, dd, J=8.4, 5.4 Hz), 4.50(1H, dd, J=9.0, 5.7 Hz), 4.85 (1H, t, J=8.7 Hz), 6.40 (1H, s), 7.07 (2H,d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2113-(4-Isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan

Using 3-(4-isopropylphenyl)-4-methyl-7,8-dihydro-6H-indeno[4,5-b]furanobtained in Reference Example 197, the title compound was synthesized inthe same manner as in Reference Example 199. Yield 59%. Melting point:77-78° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s), 2.10 (2H,quintet, J=7.5 Hz), 2.75-2.95 (5H, m), 4.40-4.54 (2H, m), 4.86 (1H, t,J=8.1 Hz), 6.57 (1H, s), 7.06 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2123-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene

Using 3-(4-isopropylphenyl)-4,6-dimethyl-1-benzothiophene obtained inReference Example 198, the title compound was synthesized in the samemanner as in Reference Example 199. Yield 85%. Melting point: 74-75° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.96 (3H, s), 2.28 (3H, s),2.85 (1H, septet, J=6.9 Hz), 3.15 (1H, dd, J=11.1, 2.4 Hz), 3.90 (1H,dd, J=11.1, 8.4 Hz), 4.64 (1H, dd, J=8.4, 2.4 Hz), 6.63 (1H, s), 6.95(1H, s), 7.02 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz)

REFERENCE EXAMPLE 2132-(4-Isopropylbenzyl)-1-methoxy-3,5-dimethylbenzene

To a mixed solution of sodium hydride (a 60% liquid paraffin dispersion,757 mg, 18.9 mmol) in DMF (50 mL) was added dropwise2-(4-isopropylbenzyl)-3,5-dimethylphenol obtained in Reference Example148 (4.01 g, 15.8 mmol) in DMF (15 mL) under argon atmosphere at 0° C.,and the mixture was stirred for 30 minutes. To the reaction solution wasadded dropwise a solution of methyl iodide (2.69 mL, 18.9 mmol) in DMF(8 mL) at the same temperature, and the mixture was stirred for 30minutes. The reaction solution was warmed to room temperature, water wasadded thereto, which was extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous sodium sulfate, filtered,and then concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=8:1) to obtain 3.49 g (yield 82%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.19 (3H, s), 2.31 (3H, s),2.83 (1H, septet, J=6.9 Hz), 3.78 (3H, s), 3.97 (2H, s), 6.59 (1H, s),6.61 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.06 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 214 1-(Allyloxy)-3,5-dimethylbenzene

Using 3,5-dimethylphenol and allyl bromide, the title compound wassynthesized in the same manner as in Reference Example 213. Yield 78%.Oily matter.

¹H-NMR (CDCl₃) δ: 2.28 (6H, s), 4.48-4.52 (2H, m), 5.24-5.29 (1H, m),5.36-5.43 (1H, m), 5.99-6.10 (1H, m), 6.55 (2H, s), 6.60 (1H, s).

REFERENCE EXAMPLE 215 2-Allyl-3,5-dimethylphenol

A solution of 1-(allyloxy)-3,5-dimethylbenzene obtained in ReferenceExample 214 (1.0 g, 6.2 mmol) in N,N-diethylaniline (4 mL) was stirredunder argon atmosphere at 210° C. for 5 hours. To the reaction solutionwas added ethyl acetate, and the mixture was washed with hydrochloricacid and a saturated brine, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane-ethylacetate 7:3) to obtain 938 mg (yield 94%) of the title compound. Oilymatter.

¹H-NMR (CDCl₃) δ: 2.24 (6H, s), 3.37-3.40 (2H, m), 4.79 (1H, s),4.98-5.08 (2H, m), 5.88-6.01 (1H, m), 6.50 (1H, s), 6.50 (1H, s).

REFERENCE EXAMPLE 216 2,4,6-Trimethyl-2,3-dihydro-1-benzofuran

To a solution of 2-allyl-3,5-dimethylphenol obtained in ReferenceExample 215 (935 mg, 5.77 mmol) in methanol (5 mL) was addedconcentrated hydrochloric acid (5 mL), and the mixture was heated underreflux under argon atmosphere for 20 hours. The reaction solution wasneutralized by aqueous sodium hydroxide solution, which was extractedwith ethyl acetate. The organic layer was washed with a saturated sodiumhydrogen carbonate solution, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure to obtain theresidue, which was purified by silica gel column chromatography (ethylacetate:hexane=1:4) to obtain 472 mg (yield 50%) of the title compound.Oily matter.

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=6.3 Hz), 2.18 (3H, s), 2.26 (3H, s),2.67 (1H, dd, J=7.5, 15.0 Hz), 3.19 (1H, dd, J=8.7, 15.0 Hz), 4.86-4.96(1H, m), 6.41 (1H, s), 6.47 (1H, s).

REFERENCE EXAMPLE 217 1-Bromo-2-(2-chloroethoxy)-2,4-dimethylbenzene

A mixed solution of 2-bromo-3,5-dimethylphenol obtained in ReferenceExample 149 (16.3 g, 74.6 mmol) and benzyl-tri-n-butylammonium chloride(23.3 g, 7.46 mmol) in 1,2-dichloroethane (150 mL)—a 8 N aqueous sodiumhydroxide solution (26 mL)—water (110 mL), was heated under reflux for 5hours. Water was added to the reaction solution, which was extractedwith ethyl acetate. The combined organic layer was washed with water, asaturated sodium hydrogen carbonate solution, and a saturated brine,dried over anhydrous sodium sulfate, filtered, and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to obtain 16.6 g (yield 90%)of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 2.28 (3H, s), 2.37 (3H, s), 3.85 (2H, t, J=6.3 Hz),4.25 (2H, t, J=6.3 Hz), 6.57 (1H, s), 6.73 (1H, s).

REFERENCE EXAMPLE 2182-Bromo-3-(2-chloroethoxy)-4-(4-isopropylphenyl)-1,5-dimethylbenzene

Using 2-bromo-6-(4-isopropylbenzyl)-3,5-dimethylphenol obtained inReference Example 150, the title compound was synthesized in the samemanner as in Reference Example 217.

Yield: quantitative. Oily matter.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 2.15 (3H, s), 2.37 (3H, s),2.85 (1H, septet, J=6.9 Hz), 3.75 (2H, t, J=6.0 Hz), 3.98-4.07 (4H, m),6.89 (1H, s), 7.00 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 219 4,6-Dimethyl-2,3-dihydro-1-benzofuran

To a solution of 1-bromo-2-(2-chloroethoxy)-2,4-dimethylbenzene obtainedin Reference Example 217 (8.70 g, 33.0 mmol) in THF (210 mL) was quicklyadded n-butyllithium (1.6 M hexane solution, 31 mL, 49.5 mmol) underargon atmosphere at 0° C., and the mixture was stirred for 30 minutes.The reaction solution was warmed to room temperature, to which ice wasadded, which was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, was filtered, and then wasconcentrated under reduced pressure to obtain 4.70 g (yield 96%) of thetitle compound. Oily matter.

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.26 (3H, s), 3.06 (2H, t, J=8.7 Hz),4.54 (2H, t, J=8.7 Hz), 6.45 (1H, s), 6.48 (1H, s).

REFERENCE EXAMPLE 2207-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using2-bromo-3-(2-chloroethoxy)-4-(4-isopropylphenyl)-1,5-dimethylbenzeneobtained in Reference Example 218, the title compound was synthesized inthe same manner as in Reference Example 219. Yield 81%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.17 (3H, s), 2.19 (3H, s),2.83 (1H, septet, J=6.9 Hz), 3.11 (2H, t, J=8.7 Hz), 3.90 (2H, s), 4.56(2H, t, J=8.7 Hz), 6.49 (1H, s), 7.07 (4H, s).

REFERENCE EXAMPLE 2215-Bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran

Using 7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 200, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 87%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 2.30(3H, s), 2.35 (3H, s), 2.80-2.90 (1H, septet, J=6.9 Hz), 3.40-3.55 (1H,m), 3.98 (2H, s), 4.21 (1H, dd, J=3.0, 8.7 Hz), 4.54 (1H, t, J=8.7 Hz),7.03 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 2225-Bromo-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 199, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 99%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.6 Hz), 1.20 (6H, d, J=6.9 Hz),1.49-1.64 (2H, m), 2.30 (3H, s), 2.34 (3H, s), 2.84 (1H, septet, J=6.9Hz), 3.31-3.37 (1H, m), 3.97 (2H, s), 4.38 (1H, dd, J=3.0, 8.7 Hz), 4.48(1H, t, J=8.7 Hz), 7.04 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2235-Bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran

Using7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuranobtained in Reference Example 201, the title compound was synthesized inthe same manner as in Reference Example 23. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.5 Hz), 1.20 (6H, d, J=6.9 Hz),1.22-1.42 (2H, m), 1.47-1.62 (2H, m), 2.29 (3H, s), 2.34 (3H, s), 2.84(1H, septet, J=6.9 Hz), 3.30-3.40 (1H, m), 3.98 (2H, s), 4.38 (1H, dd,J=3.3, 9.0 Hz), 4.47 (1H, t, J=9.0 Hz), 7.04 (2H, d, J=8.4 Hz), 7.09(2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 2245-Bromo-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 202, the title compound was synthesized inthe same manner as in Reference Example 23. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.9 Hz), 0.98 (3H, d, J=6.9 Hz), 1.20(6H, d, J=6.9 Hz), 2.01-2.10 (1H, m), 2.29 (3H, s), 2.34 (3H, s), 2.84(1H, septet, J=6.9 Hz), 3.34-3.39 (1H, m), 3.92 (1H, d, J=15.3 Hz), 4.02(1H, d, J=15.3 Hz), 4.36 (1H, t, J=9.0 Hz), 4.50 (1H, dd, J=2.7, 9.0Hz), 7.03 (2H, d, J=8.7 Hz), 7.08 (2H, d, J=8.7 Hz).

REFERENCE EXAMPLE 225 5-Bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran

Using 2,4,6-trimethyl-2,3-dihydro-1-benzofuran obtained in ReferenceExample 216, the title compound was synthesized in the same manner as inReference Example 23.

Yield 89%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.44 (3H, d, J=6.3 Hz), 2.28 (3H, s), 2.35 (3H, s),2.74 (1H, dd, J=7.5, 15.0 Hz), 3.26 (1H, dd, J=8.7, 15.0 Hz), 4.85-4.97(1H, m), 6.52 (1H, s).

REFERENCE EXAMPLE 226 5-Bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using 4,6-dimethyl-2,3-dihydro-1-benzofuran obtained in ReferenceExample 219, the title compound was synthesized in the same manner as inReference Example 23.

Yield 92%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.31 (3H, s), 2.35 (3H, s), 3.15 (2H, t, J=8.7 Hz),4.56 (2H, t, J=8.7 Hz), 6.56 (1H, s).

REFERENCE EXAMPLE 2275-Bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran

Using 7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 220, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 92%. Melting point:95-96° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.31 (6H, s), 2.84 (1H,septet, J=6.9 Hz), 3.19 (2H, t, J=8.4 Hz), 3.97 (2H, s), 4.56 (2H, t,J=8.7 Hz), 7.04 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 228 3-Phenyl-4,6,7-trimethyl-1-benzofuran-2(3H)-one

Using 2,3,5-trimethylphenol and hydroxy(phenyl)acetic acid, the titlecompound was synthesized in the same manner as in Reference Example 2.Yield 37%. Melting point: 129-130° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.92 (3H, s), 2.25 (3H, s), 2.30 (3H, s), 4.80 (1H,s), 6.78 (1H, s), 7.16-7.20 (2H, m), 7.27-7.40 (3H, m).

REFERENCE EXAMPLE 2293-(4-Bromophenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one

Using 2,3,5-trimethylphenol and hydroxy(4-bromophenyl)acetic acid, thetitle compound was synthesized in the same manner as in ReferenceExample 2. Yield 43%. Melting point: 168-169° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.93 (3H, s), 2.24 (3H, s), 2.30 (3H, s), 4.76 (1H,s), 6.79 (1H, s), 7.06 (2H, d, J=8.1 Hz), 7.47 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2303-(4-Isopropylphenyl)-4,7-dimethyl-1-benzofuran-2(3H)-one

Using hydroxy(4-isopropylphenyl)acetic acid and 2,5-dimethylphenolsynthesized in Reference Example 1, the title compound was synthesizedin the same manner as in Reference Example 2. Yield 20%. Melting point:107-109° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.0 Hz), 1.97 (3H, s), 2.33 (3H, s),2.89 (1H, septet, J=7.0 Hz), 4.77 (1H, s), 6.86 (1H, d, J=7.6 Hz),7.05-7.13 (3H, m), 7.19 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 2312-(2-Hydroxy-1-(phenyl)ethyl)-3,5,6-trimethylphenol

Using 3-phenyl-4,6,7-trimethyl-1-benzofuran-2(3H)-one obtained inReference Example 228, the title compound was synthesized in the samemanner as in Reference Example 8.

Yield 82%. Melting point: 103-104° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 2.15 (3H, s), 2.19 (3H, s), 2.24 (3H, s), 4.26 (1H, d,J=10.8 Hz), 4.47 (1H, dd, J=5.1, 10.8 Hz), 4.53 (1H, br), 6.60 (1H, s),7.20-7.35 (5H, m), 8.00 (1H, br), 1H unidentified.

REFERENCE EXAMPLE 2322-(2-Hydroxy-1-(4-bromophenyl)ethyl)-3,5,6-trimethylphenol

Using 3-(4-bromophenyl)-4,6,7-trimethyl-1-benzofuran-2(3H)-one obtainedin Reference Example 229, the title compound was synthesized in the samemanner as in Reference Example 8. Yield 93%. Melting point: 114-115° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 2.13 (3H, s), 2.19 (3H, s), 2.23 (3H, s), 4.20-4.30(1H, m), 4.40-4.52 (2H, m), 6.60 (1H, s), 7.13 (2H, d, J=8.4H), 7.41(2H, d, J=8.4H), 7.72 (1H, s), 1H unidentified.

REFERENCE EXAMPLE 2332-(2-Hydroxy-1-(4-isopropylphenyl)ethyl)-3,6-dimethylphenol

Using 3-(4-isopropylphenyl)-4,7-dimethyl-1-benzofuran-2(3H)-onesynthesized in Reference Example 230, the title compound was synthesizedin the same manner as in Reference Example 8. Yield 88%. Melting point:88-89° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.21 (3H, s), 2.23 (3H, s),2.25 (1H, br s), 2.87 (1H, septet, J=6.9 Hz), 4.20-4.30 (1H, m),4.32-4.52 (2H, m), 6.65 (1H, d, J=7.2 Hz), 6.96 (1H, d, J=7.2 Hz), 7.17(4H, s), 8.18 (1H, br s).

REFERENCE EXAMPLE 2343-Bromo-6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,4,5-trimethylphenol

To a mixture of hydroxy(4-isopropylphenyl)acetic acid (10.0 g, 46.5mmol) synthesized in Reference Example 1 and3-bromo-2,4,5-trimethylphenol synthesized in Reference Example 68 (8.2g, 42.2 mmol) was added 70% sulfuric acid (10 mL) at room temperature,and the mixture was stirred at 115° C. for 4 hours. The mixture wasadded to water, which was extracted with diisopropyl ether. The extractwas washed with water and a saturated sodium hydrogen carbonatesolution, and then was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to obtain theresidue, which was purified by silica gel column chromatography (ethylacetate:hexane=1:8) to obtain6-bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-1-benzofuran-2(3H)-one. Toa solution of the compound in THF (80 mL) was added lithium aluminumhydride (2.40 g, 63.3 mmol) at 0° C., and the mixture was heated underreflux for 1 hour. Water was added to the reaction solution, and theproduct was extracted with ethyl acetate. The combined extract waswashed with water, dried over magnesium sulfate, and then concentratedunder reduced pressure. The obtained residue was crystallized fromhexane-ethyl acetate to obtain 15.5 g (yield 97%) of the title compound.Melting point: 96-97° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.19 (3H, s), 2.38 (3H, s),2.39 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.24 (1H, dt, J=11.4, 2.7Hz), 4.42 (1H, ddd, J=11.4, 5.4, 2.7 Hz), 4.60 (1H, dd, J=5.4, 2.7 Hz),4.93 (1H, d, J=6.3 Hz), 7.13 (2H, d, J=8.7 Hz), 7.17 (2H, d, J=8.7 Hz),8.27 (1H, br s).

REFERENCE EXAMPLE 235 4,6,7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran

Using 2-(2-hydroxy-1-(phenyl)ethyl)-3,5,6-trimethylphenol obtained inReference Example 231, the title compound was synthesized in the samemanner as in Reference Example 13. Yield 95%. Melting point: 72-73° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.16 (3H, s), 2.23 (3H, s), 4.43 (1H,dd, J=5.1, 9.0 Hz), 4.55 (1H, dd, J=5.1, 9.0 Hz), 4.86 (1H, t, J=9.0Hz), 6.49 (1H, s), 7.13-7.31 (5H, m).

REFERENCE EXAMPLE 2363-(4-Bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using 2-(2-hydroxy-1-(4-bromophenyl)ethyl)-3,5,6-trimethylphenolobtained in Reference Example 232, the title compound was synthesized inthe same manner as in Reference Example 13. Yield 95%. Melting point:72-73° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 4.36 (1H,dd, J=5.1, 9.0 Hz), 4.50 (1H, dd, J=5.1, 9.0 Hz), 4.83 (1H, t, J=9.0Hz), 6.49 (1H, s), 7.01 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.7 Hz).

REFERENCE EXAMPLE 2373-(4-Isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran

Using 2-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-3,6-dimethylphenolsynthesized in Reference Example 233, the title compound was synthesizedin the same manner as in Reference Example 13. Yield 85%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.0 Hz), 1.92 (3H, s), 2.29 (3H, s),2.86 (1H, septet, J=7.0 Hz), 4.35-4.53 (2H, m), 4.75-4.90 (1H, m), 6.47(1H, s), 6.55 (1H, s), 7.05 (2H, d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 2386-Bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran

Using3-bromo-6-(2-hydroxy-1-(4-isopropylphenyl)ethyl)-2,4,5-trimethylphenolsynthesized in Reference Example 234, the title compound was synthesizedin the same manner as in Reference Example 13. Yield 57%. Melting point:56-57° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.95 (3H, s), 2.28 (3H, s),2.32 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd, J=8.7, 4.8 Hz),4.50 (1H, dd, J=9.0, 4.2 Hz), 4.81 (1H, t, J=8.7 Hz), 7.01 (2H, d, J=8.1Hz), 7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2395-Bromo-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran

Using 4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran obtained inReference Example 235, the title compound was synthesized in the samemanner as in Reference Example 23. Yield 79%. Melting point: 107-108° C.(methanol).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 4.41 (1H,dd, J=4.5, 9.0 Hz), 4.59 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0Hz), 7.08-7.13 (2H, m), 7.18-7.34 (3H, m).

REFERENCE EXAMPLE 2405-Bromo-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran

Using 4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuranobtained in Reference Example 206, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 96%. Melting point:108-109° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.03 (3H, s), 2.23 (3H, s), 2.31 (3H, s), 2.38 (3H,s), 4.38 (1H, dd, J=4.8, 8.4 Hz), 4.55 (1H, dd, J=4.8, 8.4 Hz), 4.82(1H, t, J=8.4 Hz), 6.99 (2H, d, J=8.0 Hz), 7.09 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 2415-Bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 237, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 77%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.0 Hz), 1.99 (3H, s), 2.21 (3H, s),2.87 (1H, septet, J=7.0 Hz), 4.43 (1H, dd, J=8.2, 4.8 Hz), 4.53 (1H, dd,J=9.0, 4.4 Hz), 4.85 (1H, t, J=8.3 Hz), 7.02 (2H, d, J=8.2 Hz), 7.14(2H, d, J=8.2 Hz), 7.19 (1H, s).

REFERENCE EXAMPLE 2425-Methyl-2-(5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridine

Using 5-methyl-2-(4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridineobtained in Reference Example 207, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 84%. Melting point:105-106° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.06 (3H, s), 2.22 (3H, s), 2.29 (3H, s), 2.37 (3H,s), 4.63 (1H, dd, J=4.5, 9.0 Hz), 4.76 (1H, dd, J=4.5, 9.0 Hz), 4.87(1H, t, J=9.0 Hz), 6.86 (1H, d, J=8.1 Hz), 7.37 (1H, d, J=8.1 Hz), 8.37(1H, s).

REFERENCE EXAMPLE 2433-(Biphenyl-4-yl)-5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

A mixed solution of3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained inReference Example 236 (1.0 g, 3.15 mmol), phenylboronic acid (500 mg,4.10 mmol), tetrakis(triphenylphosphine)palladium(O) (73 mg, 0.063 mmol)in 2 N sodium carbonate aqueous solution (4 mL)-ethanol (4 mL)-toluene(15 mL) was reacted under argon atmosphere at 80° C. for 5 hours. Waterwas added to the reaction solution, which was extracted with ethylacetate.

The combined organic layer was washed with a saturated brine, was driedover anhydrous sodium sulfate, and then was concentrated under reducedpressure to obtain the residue, which was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to obtain(3-biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

750 mg (yield 76%). Using this compound, 873 mg of the title compoundwas synthesized in the same manner as in Reference Example 23. Yield93%. Melting point: 153-154° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.08 (3H, s), 2.26 (3H, s), 2.40 (3H, s), 4.46 (1H,dd, J=5.0, 9.0 Hz), 4.62 (1H, dd, J=5.0, 9.0 Hz), 4.88 (1H, t, J=9.0Hz), 7.15-7.60 (9H, m).

REFERENCE EXAMPLE 2442-Bromo-4-(4-isopropylbenzyl)-5-methoxy-1,3-dimethylbenzene

To a solution of 2-(4-isopropylbenzyl)-1-methoxy-3,5-dimethylbenzeneobtained in Reference Example 213 (3.45 g, 12.9 mmol) in acetonitrile(40 mL) was added N-bromosuccinimide (2.29 g, 12.9 mmol) withice-cooling, and the mixture was stirred for 30 minutes. Water was addedto the reaction solution, which was extracted with ethyl acetate, andthen the organic layer was dried over anhydrous sodium sulfate, wasfiltered, and then was concentrated under reduced pressure.

Ethyl acetate-hexane (1:9) was added to the residue, and theprecipitated crystals were filtered, and the filtrate was concentratedto obtain 4.50 g (yield is quantitative) of the title compound. Oilymatter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.34 (3H, s), 2.42 (3H, s),2.84 (1H, septet, J=6.9 Hz), 3.78 (3H, s), 4.06 (2H, s), 6.70 (1H, s),7.00 (2H, d, J=8.1 Hz), 7.04 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 245 3-(3-Formylphenyl)-4,6,7-trimethyl-1-benzofuran

To a solution of3-(3-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained inReference Example 203 (1.77 g, 5.57 mmol) in THF (20 mL) was addeddropwise n-butyllithium (1.6 M hexane solution, 4.18 mL, 6.68 mmol)under argon atmosphere at −78° C., and the mixture was stirred for 30minutes. To the reaction solution was added dropwise DMF (0.86 mL, 11.14mmol) at the same temperature, and the mixture was stirred for 30minutes, and then was warmed to room temperature. Water was added to thereaction solution, which was extracted with ethyl acetate, and then theorganic layer was dried over anhydrous sodium sulfate, was filtered, andthen was concentrated under reduced pressure to give 1.48 g (yield isquantitative) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.17 (3H, s), 2.24 (3H, s), 4.42 (1H,dd, J=4.5, 9.0 Hz), 4.63 (1H, dd, J=4.5, 9.0 Hz), 4.88 (1H, t, J=9.0Hz), 6.50 (1H, s), 7.39-7.49 (2H, m), 7.67-7.69 (1H, m), 7.73-7.76 (1H,m), 9.98 (1H, s).

REFERENCE EXAMPLE 2463-(4-Formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 236, the title compound was synthesized inthe same manner as in Reference Example 245. Yield 73%. Melting point:87-88° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.17 (3H, s), 2.24 (3H, s), 4.43 (1H,dd, J=4.5, 9.0 Hz), 4.62 (1H, dd, J=4.5, 9.0 Hz), 4.88 (1H, t, J=9.0Hz), 6.51 (1H, s), 7.32 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz), 9.98(1H, s).

REFERENCE EXAMPLE 2473-(3-(1,3-(Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

A solution of 3-(3-formylphenyl)-4,6,7-trimethyl-1-benzofuran obtainedin Reference Example 245 (1.48 g, 5.57 mmol), ethylene glycol (0.62 mL,11.14 mmol) and p-toluenesulfonic acid monohydrate (50 mg) in toluene(20 mL) was heated under reflux using Dean-Starks apparatus for 16hours. The reaction solution was diluted with ethyl acetate, was washedwith water and a saturated brine, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure to obtain 1.52 g(yield 88%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.87 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.98-4.13(4H, m), 4.39 (1H, dd, J=5.4, 9.0 Hz), 4.57 (1H, dd, J=5.4, 9.0 Hz),4.85 (1H, t, J=9.0 Hz), 5.75 (1H, s), 6.47 (1H, s), 7.08-7.12 (1H, m),7.25-7.35 (3H, m).

REFERENCE EXAMPLE 2483-(4-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 246, the title compound was synthesized inthe same manner as in Reference Example 247. Yield 73%. Melting point:107-108° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.87 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.97-4.16(4H, m), 4.39 (1H, dd, J=4.5, 8.4 Hz), 4.56 (1H, dd, J=4.5, 8.4 Hz),4.85 (1H, t, J=8.4 Hz), 5.77 (1H, s), 6.48 (1H, s), 7.17 (2H, d, J=8.4Hz), 7.40 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 2495-Bromo-3-(3-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using3-(3-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 247, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 73%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.02 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 4.00-4.16(4H, m), 4.39 (1H, dd, J=4.5, 9.0 Hz), 4.62 (1H, dd, J=4.5, 9.0 Hz),4.84 (1H, t, J=9.0 Hz), 5.76 (1H, s), 7.05-7.09 (1H, m), 7.26-7.38 (3H,m).

REFERENCE EXAMPLE 2505-Bromo-3-(4-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using3-(4-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 248, the title compound was synthesized inthe same manner as in Reference Example 23. Yield: quantitative. Meltingpoint: 146-147° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.01 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 4.00-4.15(4H, m), 4.38 (1H, dd, J=4.5, 9.0 Hz), 4.60 (1H, dd, J=4.5, 9.0 Hz),4.83 (1H, t, J=9.0 Hz), 5.77 (1H, s), 7.13 (2H, d, J=8.4 Hz), 7.40 (2H,d, J=8.4 Hz).

REFERENCE EXAMPLE 2515-Bromo-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran

Using3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 205, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 96%. Melting point:102-103° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 2.07 (3H, s), 2.22 (3H, s),2.39 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.87 (3H, s), 4.33 (1H, dd,J=3.3, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 4.90 (1H, dd, J=3.3, 9.0 Hz),6.60 (1H, d, J=7.5 Hz), 6.67 (1H, d, J=7.5 Hz), 6.74 (1H, s).

REFERENCE EXAMPLE 2523-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ol

Using 3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ylacetate synthesized in Reference Example 209, the title compound wassynthesized in the same manner as in Reference Example 175. Yield 91%.Melting point: 94-96° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.04 (3H, s), 2.86 (1H,septet, J=6.9 Hz), 4.52-4.74 (3H, m), 4.92-5.08 (1H, m), 7.04 (2H, d,J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.35-7.53 (2H, m), 7.91-8.12 (2H, m).

REFERENCE EXAMPLE 2533-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yltrifluoromethanesulfonate

To a solution of3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-olobtained in Reference Example 252 (2.60 g, 8.17 mmol) and4-dimethylaminopyridine (2.0 g, 16.3 mmol) in pyridine (30 mL) was addedanhydrous trifluoromethanesulfonate (1.51 mL, 9.00 mmol) at roomtemperature at 0° C., and the mixture was stirred at 50° C. for 8 hours.Water was added to the reaction solution to separate the organic layer,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layer was washed with 1 N hydrochloric acid and a saturatedsodium hydrogen carbonate solution, dried over magnesium sulfate,filtered, and then concentrated under reduced pressure to obtain 2.8 g(yield 76%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=7.0 Hz), 2.16 (3H, s), 2.87 (1H,septet, J=7.0 Hz), 4.62-4.80 (2H, m), 5.10 (1H, t, J=9.0 Hz), 7.04 (2H,d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz), 7.46-7.64 (2H, m), 7.96-8.05 (2H,m).

REFERENCE EXAMPLE 2543-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan

To a solution of3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yltrifluoromethanesulfonate obtained in Reference Example 253 (2.23 g,4.96 mmol), dichlorobis(triphenylphosphine)palladium (210 mg, 0.30mmol), 1,3-bis(diphenylphosphino)propane (310 mg, 0.750 mmol) andtributylamine (5 mL, 21 mmol) in toluene (15 mL) was added formic acid(0.5 mL) at room temperature, and the mixture was stirred under argonatmosphere at 90° C. for 16 hours. Water was added to the reactionsolution, which was extracted with ethyl acetate, the organic layer waswashed with water and a saturated brine and then was dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:20) to obtain 270 mg (yield 18%)of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.11 (3H, s), 2.86 (1H,septet, J=6.9 Hz), 4.64 (1H, dd, J=8.7, 4.8 Hz), 4.72 (1H, dd, J=9.3,5.1 Hz), 5.06 (1H, t, J=8.7 Hz), 7.07 (2H, d, J=8.1 Hz), 7.13 (2H, d,J=8.1 Hz), 7.14 (1H, s), 7.39-7.48 (2H, m), 7.70-7.76 (1H, m), 7.94-8.02(1H, m).

REFERENCE EXAMPLE 2555-Bromo-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan

Using 3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furanobtained in Reference Example 254, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 88%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.26 (3H, s), 2.87 (1H,septet, J=6.9 Hz), 4.64 (1H, dd, J=8.7, 4.5 Hz), 4.75 (1H, dd, J=9.6,4.5 Hz), 5.05 (1H, t, J=8.7 Hz), 7.03 (2H, d, J=8.1 Hz), 7.13 (2H, d,J=8.1 Hz), 7.40-7.62 (2H, m), 7.98 (1H, d, J=8.1 Hz), 8.24 (1H, d, J=8.4Hz).

REFERENCE EXAMPLE 2567-Bromo-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 208, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 95%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s), 2.14 (3H, s),2.40 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.48 (1H, dd, J=8.4, 4.5 Hz),4.63 (1H, dd, J=9.0, 4.5 Hz), 4.90 (1H, t, J=9.0 Hz), 7.04 (2H, d, J=8.1Hz), 7.13 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2575-Bromo-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan

Using3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furanobtained in Reference Example 210, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 85%. Melting point:108-109° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.68-1.90 (4H, m), 2.03 (3H,s), 2.60-2.89 (4H, m), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd, J=8.7,4.8 Hz), 4.54 (1H, dd, J=9.0, 4.5 Hz), 4.83 (1H, t, J=9.0 Hz), 7.01 (2H,d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2585-Bromo-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan

Using3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furanobtained in Reference Example 211, the title compound was synthesized inthe same manner as in Reference Example 23. Yield 84%. Melting point:127-128° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.01 (3H, s), 2.13 (2H,quintet, J=7.5 Hz), 2.80-3.03 (5H, m), 4.45 (1H, dd, J=8.7, 4.8 Hz),4.53 (1H, dd, J=9.0, 4.8 Hz), 4.86 (1H, t, J=8.7 Hz), 7.03 (2H, d, J=8.1Hz), 7.14 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2595-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene

To a mixture of3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophenesynthesized in Reference Example 212 (4.45 g, 15.8 mmol) and iron powder(59 mg, 1.05 mmol) in dichloromethane (20 mL) was added bromine (0.81mL, 15.8 mmol) at 0° C., and the mixture was stirred at the sametemperature for 1 hour. Water was poured into the reaction mixture,which was extracted with ethyl acetate.

The extract was washed with a saturated sodium hydrogen carbonatesolution and water, was dried over magnesium sulfate, was filtered andthen was concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:10)to obtain 4.6 g (yield 80%) of the title compound. Melting point:98-100° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.12 (3H, s), 2.39 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.15 (1H, dd, J=11.1, 1.8 Hz), 3.93 (1H,dd, J=11.1, 8.7 Hz), 4.64 (1H, d, J=8.7 Hz), 7.01 (2H, d, J=8.1 Hz),7.05 (1H, s), 7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 260 4,6,7-Trimethyl-1-benzofuran-3(2H)-one

Using (2,3,5-trimethylphenoxy)acetic acid obtained in Reference Example158, the title compound was synthesized in the same manner as inReference Example 41. Yield 75%. Melting point: 92-93° C. (hexane).

¹H-NMR (CDCl₃) δ: 2.17 (3H, s), 2.30 (3H, s), 2.53 (3H, s), 4.58 (2H,s), 6.64 (1H, s).

REFERENCE EXAMPLE 261 5-Bromo-4,6,7-trimethyl-1-benzofuran-3-yltrifluoromethanesulfonate

Using 4,6,7-trimethyl-1-benzofuran-3(2H)-one obtained in ReferenceExample 260, 5-bromo-4,6,7-trimethyl-1-benzofuran-3(2H)-one wassynthesized in the same manner as in Reference Example 23. Yield 86%. Toa solution of this compound (1.0 g, 5.7 mmol) in dichloromethane (10 mL)was added dropwise diisopropylethylamine (1.14 mL, 6.53 mmol) underargon atmosphere at −30° C. To the reaction solution was added dropwisetrifluoromethanesulfonic anhydride (0.96 mL, 5.70 mmol), and the mixturewas warmed to room temperature, and then was stirred for 16 hours. Waterwas added to the reaction solution, which was extracted with ethylacetate. The combined organic layer was washed with a saturated brine,was dried over anhydrous sodium sulfate, and then was concentrated underreduced pressure, the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to synthesize 1.38 g (yield63%) of the title compound. Melting point: 54-55° C. (hexane),

¹H-NMR (CDCl₃) δ: 2.46 (3H, s), 2.50 (3H; s), 2.64 (3H, s), 7.77 (1H,s).

REFERENCE EXAMPLE 2625-Bromo-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran

A mixed solution of 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yltrifluoromethanesulfonate obtained in Reference Example 261 (1.35 g,3.49 mmol), 4-ethylphenyl boronic acid (523 mg, 3.49 mmol),tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.07 mmol) in a 2 Naqueous sodium carbonate solution (4 mL)-ethanol (4 mL)-toluene (15 mL)was reacted under argon atmosphere at 80° C. for 5 hours. Water wasadded to the reaction solution, which was extracted with ethyl acetate.The combined organic layer was washed with a saturated brine, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure,the residue was purified by silica gel column chromatography (hexane) toobtain 1.10 g (yield 92%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.5 Hz), 2.30 (3H, s), 2.52 (6H, s),2.72 (2H, q, J=7.5 Hz), 7.25 (2H, d, J=8.1 Hz), 7.32 (2H, d, J=8.1 Hz),7.48 (1H, s).

REFERENCE EXAMPLE 263N-Benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 221, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 84%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.28 (3H, d, J=6.9 Hz), 2.16(3H, s), 2.24 (3H, s), 2.80-2.90 (1H, septet, J=6.9 Hz), 3.40-3.55 (1H,m), 3.85-3.95 (4H, m), 4.17 (1H, dd, J=3.3, 8.7 Hz), 4.53 (1H, t, J=8.7Hz), 7.07 (4H, s), 7.25-7.38 (5H, m) 1H unidentified.

REFERENCE EXAMPLE 264N-Benzyl-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 222, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 76%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.5 Hz), 1.20 (6H, d, J=6.9 Hz),1.50-1.66 (2H, m), 2.15 (3H, s), 2.21 (3H, s), 2.84 (1H, septet, J=6.9Hz), 2.88 (1H, br), 3.26-3.37 (1H, m), 3.87-4.00 (4H, m), 4.34 (1H, dd,J=3.0, 9.0 Hz), 4.46 (1H, t, J=9.0 Hz), 7.06 (4H, s), 7.25-7.38 (5H, s).

REFERENCE EXAMPLE 265N-Benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuranobtained in Reference Example 223, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 85%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.94 (3H, t, J=7.2 Hz), 1.21 (6H, d, J=6.9 Hz),1.27-1.42 (2H, m), 1.50-1.63 (2H, m), 2.15 (3H, s), 2.22 (3H, s), 2.84(1H, septet, J=6.9 Hz), 2.89 (1H, br), 3.30-3.39 (1H, m), 3.93 (2H, s),4.34 (1H, dd, J=3.3, 9.0 Hz), 4.45 (1H, t, J=9.0 Hz), 7.08 (4H, s), 7.09(2H, d, J=8.4 Hz), 7.16-7.40 (5H, m).

REFERENCE EXAMPLE 266N-Benzyl-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 224, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 73%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.21(6H, d, J=6.9 Hz), 2.01-2.10 (1H, m), 2.14 (3H, s), 2.19 (3H, s), 2.84(1H, septet, J=6.9 Hz), 2.90 (1H, br), 3.30-3.35 (1H, m), 3.81-4.01 (4H,m), 4.34 (1H, t, J=9.0 Hz), 4.47 (1H, dd, J=2.7, 9.0 Hz), 7.06 (4H, s),7.24-7.36 (5H, m).

REFERENCE EXAMPLE 267N-Benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylaniline

Using 5-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran obtained inReference Example 244, the title compound was synthesized in the samemanner as in Reference Example 24.

Yield: quantitative. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.19 (3H, s), 2.28 (3H, s),2.84 (1H, septet, J=6.9 Hz), 3.76 (3H, s), 3.95 (2H, s), 4.02 (2H, s),6.63 (1H, s), 7.01 (2H, d, J=8.1 Hz), 7.07 (2H, d, J=8.1 Hz), 7.24-7.37(5H, m), 1H unidentified.

REFERENCE EXAMPLE 268N-Benzyl-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using 4-bromo-2-(4-isopropylbenzyl)-1-methoxy-3,5-dimethylbenzeneobtained in Reference Example 225, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 70%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.45 (3H, d, J=6.3 Hz), 2.19 (3H, s), 2.23 (3H, s),2.70 (1H, dd, J=7.5, 15.0 Hz), 3.21 (1H, dd, J=8.7, 15.0 Hz), 3.95 (2H,s), 4.85-4.97 (1H, m), 6.45 (1H, s), 7.25-7.41 (5H, m), 1H unidentified.

REFERENCE EXAMPLE 269N-Benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amine

Using 5-bromo-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuranobtained in Reference Example 190, the title compound was obtained inthe same manner as in Reference Example 24. Yield 93%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.26 (3H, s), 2.38 (3H, s),2.60 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.11 (1H, br s), 3.98 (2H,s), 4.23 (2H, s), 7.05 (4H, s), 7.24-7.41 (6H, m).

REFERENCE EXAMPLE 270N-Benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using 5-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran obtained inReference Example 226, the title compound was obtained in the samemanner as in Reference Example 24. Yield 89%. Oily matter.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.22 (3H, s), 3.10 (2H, t, J=8.7 Hz),3.96 (2H, s), 4.53 (2H, t, J=8.7 Hz), 6.49 (1H, s), 7.24-7.40 (5H, m),1H unidentified.

REFERENCE EXAMPLE 271N-Benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 227, the title compound was obtained inthe same manner as in Reference Example 24. Yield 84%. Melting point:115-116° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.15 (3H, s), 2.20 (3H, s),2.84 (1H, septet, J=6.9 Hz), 3.14 (2H, t, J=8.7 Hz), 3.92 (2H, s), 3.94(2H, s), 4.53 (2H, t, J=8.7 Hz), 7.07 (4H, s), 7.24-7.40 (5H, m), 1Hunidentified.

REFERENCE EXAMPLE 2725-(Benzylamino)-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one

To a solution of2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic acidobtained in Reference Example 156 (5.55 g, 16.3 mmol) in THF (50 mL) wasadded dropwise oxalyl chloride (2.13 mL, 24.5 mmol) with ice-cooling.The mixture was stirred for 20 minutes, and DMF (3 drops) was addedthereto, and the mixture was stirred with ice-cooling for 30 minutes,and then, was warmed to room temperature. The solvent was removed byconcentration under reduced pressure, and to a solution of the residuein dichloromethane (50 mL) was added aluminum chloride (3.26 g, 24.5mmol) at −78° C., and the mixture was slowly warmed to room temperature.Ice was added to the reaction solution to separate the organic layer,and the aqueous layer was extracted with ethyl acetate. The combinedorganic layer was washed with a saturated sodium hydrogen carbonatesolution, dried over anhydrous sodium sulfate, filtered, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain3.35 g (yield 64%) of7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one ascrude product. To a solution of this compound (3.35 g, 10.4 mmol) inacetonitrile (40 mL) was added N-bromosuccinimide (1.85 g, 10.4 mmol)with ice-cooling, and the mixture was stirred for 30 minutes. Thereaction solution was warmed to room temperature, to which water wasadded, which was extracted with ethyl acetate. The combined organiclayer was washed with a saturated brine, dried over anhydrous sodiumsulfate, filtered, and then concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate:hexane=1:19) to obtain 2.76 g (yield 66%) of5-bromo-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-oneas crude product. The compound (2.76 g, 6.89 mmol), palladium acetate(31 mg, 0.14 mmol) and BINAP (257 mg, 0.41 mmol) were mixed at roomtemperature, and the mixture was stirred under argon stream for 15minutes. To the reaction solution was added sodium tert-butoxide (926mg, 9.63 mmol) at room temperature, and the mixture was heated underargon stream at 110° C. for 16 hours. Water was added to the reactionsolution, which was extracted with ethyl acetate. The combined organiclayer was washed with water and a saturated brine, dried over anhydroussodium sulfate, filtered, and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:9) to obtain 675 mg (yield 23%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.57 (6H, s), 2.28 (3H, s),2.54 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.03 (1H, br s), 3.93 (2H,s), 4.04 (2H, s), 7.10 (4H, s), 7.26-7.47 (5H, m).

REFERENCE EXAMPLE 273N-Benzyl-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 251, the title compound was synthesized inthe same manner as in Example 24. Yield 98%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.90 (3H, s), 2.18 (3H, s),2.28 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.00 (1H, br s), 3.87 (3H,s), 3.95 (2H, s), 4.30 (1H, dd, J=3.3, 8.4 Hz), 4.78 (1H, t, J=8.4 Hz),4.85 (1H, dd, J=3.3, 8.4 Hz), 6.60 (1H, d, J=7.5 Hz), 6.66 (1H, d, J=7.5Hz), 6.73 (1H, s), 7.26-7.40 (5H, m).

REFERENCE EXAMPLE 274N-Benzyl-3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 249, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 90%. Melting point:97-99° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.85 (3H, s), 2.17 (3H, s), 2.26 (3H, s), 2.83 (1H, brs), 3.90 (2H, s), 4.00-4.16 (4H, m), 4.37 (1H, dd, J=4.8, 9.0 Hz), 4.59(1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 5.76 (1H, s), 7.06-7.10(1H, m), 7.23-7.36 (8H, m).

REFERENCE EXAMPLE 275N-Benzyl-3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using 3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 204,5-bromo-3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran wasobtained in the same manner as in Reference Example 23. Using thiscompound, the title compound was synthesized in the same manner as inReference Example 24. Yield 76%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.19 (3H, s), 2.26 (3H, s), 3.90 (1H,br), 3.77 (3H, s), 3.91 (2H, s), 4.38 (1H, dd, J=4.8, 8.7 Hz), 4.53 (1H,dd, J=4.8, 8.7 Hz), 4.81 (1H, t, J=8.7 Hz), 6.70-6.77 (3H, m), 7.17-7.38(6H, m).

REFERENCE EXAMPLE 276N-Benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine

Using 5-bromo-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran obtainedin Reference Example 239, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 91%. Melting point: 107-108° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.86 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.93 (1H, brs), 3.91 (2H, s), 4.38 (1H, dd, J=4.5, 9.0 Hz), 4.55 (1H, dd, J=4.5, 9.0Hz), 4.83 (1H, t, J=9.0 Hz), 7.09-7.34 (10H, m).

REFERENCE EXAMPLE 2775-Benzyl-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuranobtained in Reference Example 240, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 88%. Melting point:99-100° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.87 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.31 (3H,s), 2.91 (1H, br s), 3.90 (2H, s), 4.35 (1H, dd, J=4.5, 9.0 Hz), 4.52(1H, dd, J=4.5, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 7.01 (2H, d, J=8.4 Hz),7.08 (2H, d, J=8.4 Hz), 7.23-7.40 (5H, m).

REFERENCE EXAMPLE 278N-Benzyl-4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amine

Using5-methyl-2-(5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)pyridineobtained in Reference Example 242, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 79%. Melting point:104-105° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.19 (3H, s), 2.26 (3H, s), 2.30 (3H,s), 2.92 (1H, br s), 3.91 (2H, s), 4.52 (1H, dd, J=4.5, 8.4 Hz), 4.73(1H, dd, J=4.5, 8.4 Hz), 4.85 (1H, t, J=8.4 Hz), 6.84 (1H, d, J=7.8 Hz),7.25-7.37 (6H, m), 8.36 (1H, s).

REFERENCE EXAMPLE 279N-Benzyl-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using 5-bromo-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 243, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 85%. Melting point:77-78° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.90 (3H, s), 2.22 (3H, s), 2.28 (3H, s), 2.94 (1H, brs), 3.92 (2H, s), 4.42 (1H, dd, J=4.4, 8.8 Hz), 4.59 (1H, dd, J=4.4, 8.8Hz), 4.85 (1H, t, J=8.8 Hz), 7.19 (2H, d, J=8.0 Hz), 7.25-7.64 (12H, m).

REFERENCE EXAMPLE 280N-Benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

Using 5-bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuranobtained in Reference Example 193, the title compound was synthesized inthe same manner as in Reference Example 24. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.18 (3H, s), 2.39 (3H, s),2.47 (3H, s), 2.97 (1H, septet, J=6.9 Hz), 3.13 (1H, br s), 3.99 (2H,s), 7.25-7.44 (10H, m).

REFERENCE EXAMPLE 281N-Benzyl-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

Using 5-bromo-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran obtained inReference Example 262, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 93%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.5 Hz), 2.17 (3H, s), 2.38 (3H, s),2.47 (3H, s), 2.71 (2H, q, J=7.5 Hz), 3.13 (1H, br s), 3.99 (2H, s),7.20-7.47 (10H, m).

REFERENCE EXAMPLE 282N-Benzyl-3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

Using 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yltrifluoromethanesulfonate obtained in Reference Example 261 and(4-isobutylphenyl)boronic acid,5-bromo-3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran wassynthesized in the same manner as in Reference Example 262. Using thiscompound, the title compound was synthesized in the same manner as inReference Example 24. Yield 74%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.94 (6H, d, J=7.0 Hz), 1.91 (1H, septet, J=6.9 Hz),2.16 (3H, s), 2.38 (3H, s), 2.47 (3H, s), 2.53 (2H, d, J=7.0 Hz), 3.12(1H, br), 3.99 (2H, s), 7.15-7.47 (10H, m).

REFERENCE EXAMPLE 283N-Benzyl-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

Using 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yltrifluoromethanesulfonate obtained in Reference Example 261 and(4-cyclohexylphenyl)boronic acid,5-bromo-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran wassynthesized in the same manner as in Reference Example 262. Using thiscompound, the title compound was synthesized in the same manner as inReference Example 24. Yield 61%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.26-1.52 (4H, m), 1.73-2.00 (6H, m), 2.17 (3H, s),2.38 (3H, s), 2.47 (3H, s), 2.50-2.60 (1H, m), 3.15 (1H, br), 3.99 (2H,s), 7.20-7.48 (10H, m).

REFERENCE EXAMPLE 284N-Benzyl-3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-(1,3-(dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 250, the title compound was synthesized inthe same manner as in Reference Example 24. Yield 88%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.85 (3H, s), 1.20 (3H, s), 2.26 (3H, s), 3.89 (2H,s), 3.98-4.17 (4H, m), 4.35 (1H, dd, J=4.4, 9.0 Hz), 4.56 (1H, dd,J=4.4, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 5.77 (1H, s), 7.14 (2H, d, J=8.0Hz), 7.25-7.41 (7H, m). 1H unidentified.

REFERENCE EXAMPLE 285N-Benzyl-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using5-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 241, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 96%. Melting point:82-83° C. (methanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s), 2.27 (3H, s),2.67-3.02 (2H, m), 3.93 (2H, s), 4.38 (1H, dd, J=8.4, 4.5 Hz), 4.49 (1H,dd, J=9.0, 4.5 Hz), 4.75-4.83 (1H, m), 6.59 (1H, s), 7.02 (2H, d, J=8.1Hz), 7.12 (2H, d, J=8.1 Hz), 7.19-7.39 (5H, m).

REFERENCE EXAMPLE 286N-Benzyl-3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine

Using6-bromo-3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 238, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 76%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.91 (3H, s), 2.13 (3H, s),2.17 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.05 (2H, s), 4.38 (1H, dd,J=8.7, 4.5 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz), 4.79 (1H, t, J=9.0 Hz),7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.21-7.42 (5H, m), 1Hunidentified.

REFERENCE EXAMPLE 287N-Benzyl-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine

Using7-bromo-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuransynthesized in Reference Example 256, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 81%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.07 (3H, s),2.19 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.23-4.52 (4H, m), 4.75 (1H,t, J=8.7 Hz), 6.99 (2H, d, J=7.8 Hz), 7.12 (2H, d, J=7.8 Hz), 7.19-7.39(5H, m), 1H unidentified.

REFERENCE EXAMPLE 288N-Benzyl-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-amine

Using5-bromo-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furansynthesized in Reference Example 255, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 53%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.95 (3H, s), 2.86 (1H,septet, J=6.9 Hz), 3.25 (1H, br s), 4.14 (2H, s), 4.60 (1H, dd, J=8.7,4.8 Hz), 4.70 (1H, dd, J=9.3, 4.8 Hz), 5.02 (1H, t, J=9.0 Hz), 7.03 (2H,d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.20-7.57 (7H, m), 7.98-8.04 (1H,m), 8.13-8.18 (1H, m).

REFERENCE EXAMPLE 289N-Benzyl-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-amine

Using5-bromo-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furansynthesized in Reference Example 257, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 84%. Melting point:98-99° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.72-1.87 (4H, m), 1.91 (3H,s), 2.60-2.78 (4H, m), 2.87 (1H, septet, J=6.9 Hz), 3.92 (2H, s), 4.41(1H, dd, J=8.7, 5.1 Hz), 4.52 (1H, dd, J=9.3, 5.1 Hz), 4.82 (1H, t,J=9.0 Hz), 7.06 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 7.20-7.40(5H, m), 1H unidentified.

REFERENCE EXAMPLE 290N-Benzyl-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-amine

Using5-bromo-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furansynthesized in Reference Example 258, the title compound was synthesizedin the same manner as in Reference Example 24. Yield 76%. Melting point:95-96° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.87 (3H, s), 2.10 (2H,quintet, J=7.5 Hz), 2.76-2.93 (6H, m), 4.05 (2H, s), 4.41 (1H, dd,J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.0, 4.8 Hz), 4.83 (1H, t, J=8.7 Hz),7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 7.20-7.37 (5H, m)

REFERENCE EXAMPLE 2913-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene-5-amine

To a solution of5-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiopheneobtained in Reference Example 259 (870 mg, 2.41 mmol) and benzophenoneimine (0.76 mL, 2.89 mmol) in toluene (15 mL) were addedtris(dibenzylideneacetone)dipalladium (22 mg, 0.024 mmol) and BINAP (45mg, 0.072 mmol) at room temperature, and the mixture was stirred underargon atmosphere for 15 minutes. To the reaction solution was addedsodium tert-butoxide (324 mg, 3.37 mmol) at room temperature, and themixture was heated under reflux under argon stream for 16 hours. Waterwas added to the reaction solution, which was extracted with ethylacetate, and the organic layer was washed with water and a saturatedbrine, was dried over anhydrous sodium sulfate, and then the solvent wasdistilled off under reduced pressure to obtain the crude product ofN-(diphenylmethylene)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-amine.This compound was dissolved in THF (10 mL), to which 1 N hydrochloricacid (2 mL) was added, and the mixture then was heated under reflux for30 minutes. The solvent was concentrated under reduced pressure toobtain the residue, which was neutralized with 1 N aqueous sodiumhydroxide solution. The product was extracted with ethyl acetate. Thecombined extract was washed with water, dried over magnesium sulfate,and then concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:10)to obtain 521 mg (yield 73%) of the title compound. Melting point:121-122° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.88 (3H, s), 2.17 (3H, s),2.85 (1H, septet, J=6.9 Hz), 3.11 (1H, dd, J=11.1, 1.8 Hz), 3.42 (2H, brs), 3.89 (1H, dd, J=11.1, 8.7 Hz), 4.64 (1H, d, J=8.7 Hz), 6.90 (1H, s),7.02 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2927-(4-Isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 263, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 84%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 1.27 (3H, d, J=7.2 Hz), 2.02(3H, br s), 2.15 (3H, br s), 2.80-2.90 (1H, septet, J=6.9 Hz), 3.29 (2H,br s), 3.44 (1H, br s), 3.95 (2H, m), 4.15 (1H, br s), 4.74 (1H, br s),7.06 (4H, s).

REFERENCE EXAMPLE 2933-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 264, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 93%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.5 Hz), 1.20 (6H, d, J=6.9 Hz),1.50-1.61 (2H, m), 2.02 (3H, s), 2.14 (3H, s), 2.83 (1H, septet, J=6.9Hz), 3.23-3.31 (3H, m), 3.94 (2H, s), 4.32 (1H, dd, J=2.7, 8.7 Hz), 4.40(1H, t, J=9.0 Hz), 7.05 (4H, s).

REFERENCE EXAMPLE 2947-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 265, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 85%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.2 Hz), 1.21 (6H, d, J=6.9 Hz),1.30-1.43 (2H, m), 1.50-1.63 (2H, m), 2.02 (3H, s), 2.14 (3H, s), 2.83(1H, septet, J=6.9 Hz), 3.30-3.39 (3H, m), 3.94 (2H, s), 4.31 (1H, dd,J=3.3, 8.7 Hz), 4.39 (1H, t, J=8.7 Hz), 7.06 (4H, s).

REFERENCE EXAMPLE 2953-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 266, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 74%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.72 (3H, d, J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.19(6H, d, J=6.9 Hz), 2.01 (3H, s), 2.01-2.08 (1H, m), 2.14 (3H, s), 2.82(1H, septet, J=6.9 Hz), 3.23-3.35 (3H, m), 3.88 (1H, d, J=15.6 Hz), 3.99(1H, d, J=15.6 Hz), 4.29 (1H, t, J=9.0 Hz), 4.44 (1H, dd, J=2.4, 9.0Hz), 7.04 (4H, s).

REFERENCE EXAMPLE 2967-(4-Isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amine

UsingN-benzyl-7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amineobtained in Reference Example 269, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 87%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 2.16 (3H, s), 2.38 (3H, s),2.44 (3H, s), 2.82 (1H, septet, J=6.9 Hz), 3.46 (2H, br s), 4.24 (2H,s), 7.06 (4H, s), 7.24 (1H, s).

REFERENCE EXAMPLE 297 4,6-Dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using N-benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained inReference Example 270, the title compound was synthesized in the samemanner as in Reference Example 30. Yield 86%. Melting point: 85-86° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 2.11 (3H, s), 2.15 (3H, s), 3.10 (2H, t, J=8.7 Hz),3.27 (2H, br s), 4.48 (2H, t, J=8.7 Hz), 6.44 (1H, s).

REFERENCE EXAMPLE 2987-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 271, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 92%. Melting point:114-115° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.19 (6H, d, J=6.9 Hz), 2.03 (3H, s), 2.11 (3H, s),2.83 (1H, septet, J=6.9 Hz), 3.14 (2H, t, J=8.7 Hz), 3.20 (2H, br), 3.95(2H, s), 4.48 (2H, t, J=8.7 Hz), 7.06 (4H, s).

REFERENCE EXAMPLE 2995-Amino-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one

Using5-(benzylamino)-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-oneobtained in Reference Example 272, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 99%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.43 (6H, s), 2.14 (3H, s),2.47 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.42 (2H, br s), 4.04 (2H,s), 7.08 (4H, s).

REFERENCE EXAMPLE 300(3-(4-Isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)amine

Using N-benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylanilineobtained in Reference Example 267, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 86%. Melting point:91-92° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.06 (3H, s), 2.21 (3H, s),2.83 (1H, septet, J=6.9 Hz), 3.26 (2H, br s), 3.73 (3H, s), 4.04 (2H,s), 6.61 (1H, s), 7.02 (2H, d, J=8.1 Hz), 7.07 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3013-(3-(1,3-(Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 274, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 81%. Melting point:138-139° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.81 (3H, s), 2.12 (3H, s), 2.20 (3H, s), 3.26 (2H, brs), 4.00-4.16 (4H, m), 4.32 (1H, dd, J=4.8, 9.0 Hz), 4.59 (1H, dd,J=4.8, 9.0 Hz), 4.77 (1H, t, J=9.0 Hz), 5.75 (1H, s), 7.08-7.12 (1H, m),7.26-7.36 (3H, m).

REFERENCE EXAMPLE 3023-(3-Methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 275, the title compound was synthesized inthe same manner as in Reference Example 30. Yield: quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 1.84 (3H, s), 2.11 (3H, s), 2.20 (3H, s), 3.26 (2H, brs), 3.75 (3H, s), 4.33 (1H, dd, J=4.8, 8.7 Hz), 4.53 (1H, dd, J=4.8, 8.7Hz), 4.76 (1H, t, J=8.7 Hz), 6.67-6.75 (3H, m), 7.18 (1H, t, J=7.8 Hz).

REFERENCE EXAMPLE 3033-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 273, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 87%. Melting point:120-121° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s), 2.13 (3H, s),2.19 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.29 (2H, br s), 3.88 (3H,s), 4.27 (1H, dd, J=3.3, 8.7 Hz), 4.73 (1H, t, J=8.7 Hz), 4.86 (1H, dd,J=3.3, 8.7 Hz), 6.65 (2H, s), 6.73 (1H, s).

REFERENCE EXAMPLE 304 2,4,6-Trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using N-benzyl-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtainedin Reference Example 268, the title compound was synthesized in the samemanner as in Reference Example 30. Yield 71%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.43 (3H, d, J=6.3 Hz), 2.09 (3H, s), 2.15 (3H, s),2.71 (1H, dd, J=7.5, 15.0 Hz), 3.18-3.27 (3H, m), 4.80-4.91 (1H, m),6.42 (1H, s).

REFERENCE EXAMPLE 3053-(4-Isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amineobtained in Reference Example 280, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 80%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=6.9 Hz), 2.08 (3H, s), 2.24 (3H, s),2.47 (3H, s), 2.97 (1H, septet, J=6.9 Hz), 3.49 (2H, br s), 7.27 (2H, d,J=7.8 Hz), 7.36 (2H, d, J=7.8 Hz), 7.42 (1H, s).

REFERENCE EXAMPLE 3064,6,7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine

Using N-benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 276, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 72%. Melting point:94-95° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.82 (3H, s), 2.11 (3H, s), 2.21 (3H, s), 3.26 (2H, brs), 4.33 (1H, dd, J=4.5, 9.0 Hz), 4.56 (1H, dd, J=4.5, 9.0 Hz), 4.77(1H, t, J=9.0 Hz), 7.11-7.29 (5H, m)

REFERENCE EXAMPLE 3074,6,7-Trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 277, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 91%. Melting point:121-122° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.83 (3H, s), 2.12 (3H, s), 2.24 (3H, s), 2.31 (3H,s), 3.26 (2H, s), 4.31 (1H, dd, J=4.5, 9.0 Hz), 4.53 (1H, dd, J=4.5, 9.0Hz), 4.76 (1H, t, J=9.0 Hz), 7.13 (2H, d, J=8.1 Hz), 7.08 (2H, d, J=8.1Hz).

REFERENCE EXAMPLE 3084,6,7-Trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 278, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 85%. Melting point:125-127° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.87 (3H, s), 2.11 (3H, s), 2.19 (3H, s), 2.29 (3H,s), 3.27 (2H, br s), 4.48 (1H, dd, J=3.9, 9.0 Hz), 4.73 (1H, dd, J=3.9,9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 6.87 (1H, d, J=7.8 Hz), 7.35 (1H, dd,J=1.8, 7.8 Hz), 8.36 (1H, d, J=1.8 Hz).

REFERENCE EXAMPLE 3093-(Biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 279, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 89%. Melting point:149-150° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.88 (3H, s), 2.13 (3H, s), 2.22 (3H, s), 3.29 (2H, brs), 4.38 (1H, dd, J=4.4, 8.8 Hz), 4.60 (1H, dd, J=4.4, 8.8 Hz), 4.81(1H, t, J=8.8 Hz), 7.20 (2H, d, J=8.2 Hz), 7.28-7.59 (7H, m).

REFERENCE EXAMPLE 3103-(4-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 284, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 87%. Melting point:125-136° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.81 (3H, s), 2.11 (3H, s), 2.20 (3H, s), 3.26 (2H, brs), 3.97-4.17 (4H, m), 4.30 (1H, dd, J=4.8, 9.0 Hz), 4.57 (1H, dd,J=4.8, 9.0 Hz), 4.77 (1H, t, J=9.0 Hz), 5.77 (1H, s), 7.15 (2H, d, J=8.0Hz), 7.42 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 3113-(4-Ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

Using N-benzyl-3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amineobtained in Reference Example 281, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 85%. Melting point:68-69° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.30 (3H, t, J=7.5 Hz), 2.07 (3H, s), 2.24 (3H, s),2.47 (3H, s), 2.72 (2H, q, J=7.5 Hz), 3.48 (2H, br s), 7.24 (2H, d,J=8.1 Hz), 7.35 (2H, d, J=8.1 Hz), 7.42 (1H, s).

REFERENCE EXAMPLE 3123-(4-Isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

Using N-benzyl-3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amineobtained in Reference Example 282, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 88%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.95 (6H, d, J=6.9 Hz), 1.94 (1H, septet, J=6.9 Hz),2.05 (3H, s), 2.24 (3H, s), 2.47 (3H, s), 2.53 (2H, d, 6.9 Hz), 3.48(2H, br s), 7.18 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.43 (1H, s)

REFERENCE EXAMPLE 3133-(4-Cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine

UsingN-benzyl-3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amineobtained in Reference Example 283, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 79%. Melting point:139-140° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.26-1.50 (4H, m), 1.74-1.92 (6H, m), 1.95 (3H, s),2.23 (3H, s), 2.47 (3H, s), 2.50-2.60 (1H, m), 3.48 (2H, br s), 7.24(2H, d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.41 (1H, s).

REFERENCE EXAMPLE 3143-(4-Ethylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using 3-(4-ethylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtained inReference Example 311, the title compound was synthesized in the samemanner as in Reference Example 144. Yield 80%. Melting point: 88-89° C.(hexane).

¹H-NMR (CDCl₃) δ: 1.21 (3H, t, J=7.5 Hz), 1.84 (3H, s), 2.12 (3H, s),2.21 (3H, s), 2.61 (2H, q, J=7.5 Hz), 3.27 (2H, br s), 4.53 (1H, dd,J=4.8, 8.4 Hz), 4.53 (1H, dd, J=4.8, 8.4 Hz), 4.76 (1H, t, J=8.4 Hz),7.05 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3153-(4-Isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 285, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 92%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.79 (3H, s), 2.18 (3H, s),2.73 (2H, br s), 2.86 (1H, septet, J=6.9 Hz), 4.36 (1H, dd, J=8.7, 4.5Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz), 4.77 (1H, t, J=8.7 Hz), 6.40 (1H, s),7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3163-(4-Isopropylphenyl)-4-5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4-5,7-trimethyl-2,3-dihydro-1-benzofuran-6-aminesynthesized in Reference Example 286, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 83%. Melting point:88-89° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s), 2.00 (3H, s),2.11 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.59 (2H, br s), 4.36 (1H,dd, J=8.7, 4.5 Hz), 4.50 (1H, dd, J=9.0, 4.2 Hz), 4.77 (1H, t, J=8.7Hz), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3173-(4-Isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-aminesynthesized in Reference Example 287, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 80%. Melting point:122-123° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s), 2.09 (3H, s),2.13 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.40 (2H, br s), 4.42 (1H,dd, J=8.7, 4.5 Hz), 4.53 (H, dd, J=9.3, 4.5 Hz), 4.81 (1H, t, J=9.3 Hz),7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3183-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-aminesynthesized in Reference Example 288, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 83%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 2.01 (3H, s), 2.86 (1H,septet, J=6.9 Hz), 3.54 (2H, br s), 4.47-4.58 (2H, m), 4.90-5.03 (1H,m), 7.04 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz), 7.30-7.50 (2H, m),7.74-7.85 (1H, m), 7.89-8.05 (1H, m).

REFERENCE EXAMPLE 3193-(4-Isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-aminesynthesized in Reference Example 289, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 76%. Melting point:106-107° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.59-1.92 (7H, m), 2.49 (2H,t, J=7.5 Hz), 2.67 (2H, t, J=7.5 Hz), 2.86 (1H, septet, J=6.9 Hz), 3.20(2H, br s), 4.36 (1H, dd, J=8.7, 5.1 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz),4.77 (1H, t, J=8.7 Hz), 7.06 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3203-(4-Isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-amine

UsingN-benzyl-3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-aminesynthesized in Reference Example 290, the title compound was synthesizedin the same manner as in Reference Example 30. Yield 91%. Melting point:112-113° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.83 (3H, s), 2.10-2.25 (2H,m), 2.68-2.98 (5H, m), 3.22 (2H, br s), 4.38 (1H, dd, J=8.4, 4.5 Hz),4.49 (1H, dd, J=8.7, 4.5 Hz), 4.79 (1H, t, J=8.7 Hz), 7.05 (2H, d, J=8.1Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 321 Ethyl3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate

To a suspension of sodium hydride (a 60% liquid paraffin dispersion, 430mg, 10.8 mmol) in DMF (50 mL) was added triethyl phosphonoacetate (2.19g, 9.78 mmol) at 0° C., and the mixture was stirred at the sametemperature for 30 minutes.

To the reaction solution was added(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 60 (3.0 g, 8.89 mmol), and the mixture was stirredat room temperature for 30 minutes. Water was added to the reactionsolution, and the product was extracted with diisopropyl ether. Thecombined extract was washed with water, dried over magnesium sulfate,and then concentrated under reduced pressure to obtain the crude productof oily ethyl(2E)-3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-2-propenoate.A mixture of said compound with 10%—palladium carbon (50% hydrous, 300mg) and ammonium formate (1.26 g, 20 mmol) in ethanol (50 mL), washeated under reflux for 2 hours. The solid material was removed and thefiltrate was concentrated under reduced pressure. Water and ethylacetate were added to the residue to separate the organic layer, and theaqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with water and was dried over magnesium sulfate andthen concentrated under reduced pressure. The solvent was distilled offunder reduced pressure to obtain the crude product of ethyl3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate.A mixture of said compound with concentrated hydrochloric acid (10mL)-ethanol (30 mL), was heated under reflux for 1.5 hours. The solventwas distilled off under reduced pressure and the obtained residue wasneutralized with a 12 N aqueous sodium hydroxide solution. The productwas extracted with ethyl acetate.

The combined extract was washed with water, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:4) to obtain 1.55 g (yield 46%) of the title compound.Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.26 (3H, t, J=7.2 Hz), 1.84(3H, s), 2.14 (3H, s), 2.53 (2H, dd, J=9.6, 6.0 Hz), 2.86 (1H, septet,J=6.9 Hz), 2.99 (2H, dd, J=9.3, 7.2 Hz), 3.26 (2H, br s), 4.14 (2H, q,J=7.2 Hz), 4.33 (1H, dd, J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.3, 4.8 Hz),4.74 (1H, t, J=9.0 Hz), 7.02 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3223-(5-Amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propan-1-ol

To a suspension of ethyl3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoatesynthesized in Reference Example 321 (1.28 g, 3.36 mmol) in THF, wasadded Lithium aluminum hydride (255 mg, 6.72 mmol) at 0° C., and themixture was stirred at the same temperature for 30 minutes and heatedunder reflux for 30 minutes. To the reaction solution was added water,and the product was extracted with ethyl acetate. The combined extractwas washed with water, dried over magnesium sulfate and thenconcentrated under reduced pressure. The obtained residue wascrystallized from hexane-ethyl acetate to obtain 750 mg (yield 66%) ofthe title compound. Melting point: 110-111° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=7.0 Hz), 1.70-1.90 (5H, m), 2.13 (3H,s), 2.70-2.91 (3H, m), 3.24 (2H, br s), 3.56 (2H, t, J=5.4 Hz), 4.36(1H, dd, J=8.4, 4.0 Hz), 4.53 (1H, dd, J=8.8, 4.4 Hz), 4.75 (1H, t,J=8.6 Hz), 7.0.2 (2H, d, J=8.0 Hz), 7.12 (2H, d, J=8.0 Hz), 1Hunidentified.

REFERENCE EXAMPLE 323(4-Bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)amine

To a solution of3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-aminesynthesized in Reference Example 31 (5.62 g, 21.1 mmol) in acetonitrile(60 mL), was added N-bromosuccinimide (3.76 g, 21.1 mmol) at −20° C.,and the mixture was stirred at the same temperature for 10 minutes. Thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:4)to obtain 0.90 g (yield 34%) of the title compound. Melting point:191-193° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 2.13 (3H, s), 2.17 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.68 (2H, br s), 4.42 (1H, dd, J=8.4, 3.9Hz), 4.50 (1H, dd, J=8.7, 3.9 Hz), 4.76 (1H, t, J=8.7 Hz), 7.07 (2H, d,J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 324 Cyclopentyl(4-isopropylphenyl)methanone

To a solution of cumene (16.4 g, 137 mmol) and aluminum chloride (21.9g, 164 mmol) in dichloromethane (200 mL) was added cyclopentanecarbonylchloride (20 g, 151 mmol) at −50° C. (the inside temperature), and themixture was stirred for two hours until the temperature reached −10° C.(the inside temperature).

The reaction solution was poured into ice-cold water to separate theorganic layer.

The organic layer was washed with a 12 N sodium hydroxide solution and asaturated brine, and then dried over sodium sulfate.

The solvent was distilled off under reduced pressure to obtain 22.5 g(yield 80%) of the title compound as oily matter.

Oily matter.

¹H-NMR (CDCl₃) δ: 1.27 (6H, d, J=6.9 Hz), 1.57-1.92 (8H, m), 2.96 (1H,septet, J=6.9 Hz), 3.69 (1H, quartet, J=7.8 Hz), 7.29 (2H, d, J=8.4 Hz),7.90 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 3253-(4-Isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1′-cyclopentane)-5-amine

To a solution of tert-butyl3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate (2.0 g, 5.81 mmol)synthesized in Reference Example 129 in THF (20 mL) was added n-butyllithium (a 1.6 M hexane solution, 8 mL, 12.8 mmol) at −78° C., and themixture was stirred at the same temperature for 20 minutes. To thereaction solution was added a solution ofcyclopentyl(4-isopropylphenyl)methanone synthesized in Reference Example324 (1.38 g, 6.39 mmol) in THF (5 mL), and the mixture was stirred atroom temperature for 1 hours. To the reaction solution was added asolution of cyclopentyl(4-isopropylphenyl)methanone synthesized inReference Example 324 (1.38 g, 6.39 mmol) in THF (5 mL), and the mixturewas stirred for 1 hours. Water was poured into the reaction mixturewhich was extracted with ethyl acetate, and the organic layer was washedwith water, dried over magnesium sulfate, filtered and then concentratedunder reduced pressure.

The obtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain tert-butyl3-(cyclopentyl(hydroxy)(4-isopropylphenyl)methyl)-4-methoxy-2,5,6-trimethylphenylcarbamate.A mixture of said compound and 47% hydrobromic acid (50 mL) was heatedunder reflux under argon atmosphere for 3 hours. The reaction mixturewas cooled to room temperature, and then neutralized with 12 N aqueoussodium hydroxide solution. The product was extracted with ethyl acetate,and the combined extract was washed with water, dried over magnesiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to obtain 400 mg (yield 22%) of the title compound. Meltingpoint: 132-133° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11-1.35 (7H, m), 1.45-1.92 (9H, m), 1.96-2.22 (7H,m), 2.84 (1H, septet, J=6.9 Hz), 3.21 (2H, br s), 4.13 (1H, s), 6.88(2H, d, J=8.1 Hz), 7.05 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 326(S)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

Using3-(4-isopropylphenyl)-3,5-dimethyl-2,3-dihydro-1-benzofuran-5-amine and-(2R,3R)-(4′-methyl)-tartranilic acid obtained in Reference Example 32,the title compound was synthesized in the same manner as in ReferenceExample 141. Yield 40%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.85 (3H, s), 2.18 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.07 (2H, br s), 4.35 (1H, dd, J=8.4, 4.5Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz), 4.71-4.80 (1H, m), 6.54 (1H, s), 7.03(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3273-(4-Isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

A mixture of(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide(800 mg, 2.06 mmol) synthesized in Example 59, copper(I) bromide (296mg, 2.06 mmol), ethyl acetate (0.402 mL, 4.12 mmol) and a 28% sodiummethoxide-methanol solution (20 mL), was heated under reflux for 6hours.

1 N hydrochloric acid was added to the reaction solution, and theproduct was extracted with ethyl acetate to obtain the crude product of(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide.This compound was dissolved in methanol (6 mL), concentratedhydrochloric acid (2 mL) was added thereto, and the mixture was heatedunder reflux for 24 hours. The solvent was distilled off under reducedpressure and the obtained residue was neutralized with a 12 N aqueoussodium hydroxide solution. The product was extracted with ethyl acetate,and the extract was washed with water, dried over magnesium sulfate andthen concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:4)to obtain 310 mg (yield 48%) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.81 (3H, s), 2.12 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.28 (2H, br s), 3.88 (3H, s), 4.39 (1H,dd, J=4.5, 8.7 Hz), 4.50 (1H, dd, J=4.2, 9.0 Hz), 4.79 (1H, t, J=8.7Hz), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3287-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

To a solution of methylmagnesium bromide (a 1.0 M THF solution, 10 mL,10 mmol) in THF was added(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 60 (600 mg, 1.78 mmol) at 0° C., and the mixture wasstirred at room temperature for 1 hour. The reaction solution was addedto water, which was extracted with ethyl acetate. The organic layer waswashed with 1 N hydrochloric acid and saturated brine, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.To a mixture of the obtained residue and trifluoroacetic acid (5 mL) wasadded triethylsilane (0.27 mL, 2.46 mmol), and the mixture was stirredat room temperature for 1 hour. The reaction solution was concentratedunder reduced pressure, and the residue was added to a saturated sodiumhydrogen carbonate solution to alkalify the aqueous layer, which wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate and thenconcentrated under reduced pressure. The obtained residue was dissolvedin methanol (6 mL), to which concentrated hydrochloric acid (2 mL) wasadded, and the mixture was heated under reflux for 24 hours. The solventwas distilled off under reduced pressure and the obtained residue wasneutralized with a 12 N aqueous sodium hydroxide solution.

The product was extracted with ethyl acetate, and the extract was washedwith water, dried over magnesium sulfate and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to obtain 250 mg (yield 45%)of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz), 1.84(3H, s), 2.14 (3H, s), 2.67 (2H, q, J=7.5 Hz), 2.86 (1H, septet, J=6.9Hz), 4.20-4.60 (2H, m), 4.61-4.82 (1H, m), 7.04 (2H, d, J=8.1 Hz), 7.11(2H, d, J=8.1 Hz), 2H unidentified.

REFERENCE EXAMPLE 3293-(4-Isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-amine

A mixture of(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 59 (1.0 g, 2.58 mmol), phenylboronic acid (345 mg,2.83 mmol) and tetrakis(triphenylphosphine)palladium (99 mg, 0.086 mmol)in 2 N sodium carbonate aqueous solution (30 mL)-1,2-dimethoxyethane (15mL) was heated under reflux under nitrogen atmosphere for 16 hours. Thereaction solution was diluted with ethyl acetate, the insolubles weretaken by filtration, and the filtrate was washed with a saturated brineand then dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure to give the crude product of(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)formamide.This compound was dissolved in methanol (18 mL), to which concentratedhydrochloric acid (6 mL) was added, and the mixture was heated underreflux for 2 hours. The solvent was distilled off under reduced pressureand the obtained residue was neutralized with a 12 N aqueous sodiumhydroxide solution. The product was extracted with ethyl acetate. Theextract was washed with water, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain642 mg (yield 70%) of the title compound. Melting point: 101-102° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s), 2.03 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.34 (2H, br s), 4.31 (1H, dd, J=4.2, 9.0Hz), 4.55 (1H, dd, J=4.8, 9.3 Hz), 4.72 (1H, t, J=8.7 Hz), 7.09 (2H, d,J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 7.28-7.45 (5H, m).

REFERENCE EXAMPLE 330N-(7-(4-Isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using5-amino-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3-(2H)-oneobtained in Reference Example 299, the title compound was synthesized inthe same manner as in Reference Example 63. Yield 86%. Melting point:193-194° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.44 (6H, s),2.20 (3H, s), 2.29 (2H, s), 2.49 (3H, s), 2.84 (1H, septet, J=6.9 Hz),4.02 (2H, s), 6.56 (1H, br s), 7.09 (4H, s).

REFERENCE EXAMPLE 331N-(7-(4-Isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 7-(4-isopropylbenzyl)-3,4,6-trimethyl-1-benzofuran-5-amineobtained in Reference Example 296, the title compound was synthesized inthe same manner as in Reference Example 63. Yield 90%. Melting point:171-172° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.16 (9H, s), 1.19 (6H, d, J=6.9 Hz), 2.21 (3H, s),2.32 (2H, s), 2.36 (3H, s), 2.56 (3H, s), 2.82 (1H, septet, J=6.9 Hz),4.22 (2H, br s), 6.64 (1H, s), 7.04 (4H, s), 7.29 (1H, s).

REFERENCE EXAMPLE 332N-Benzyl-N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide

Using N-benzyl-3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylanilineobtained in Reference Example 267, the title compound was obtained inthe same manner as in Example 63. Yield 94%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.98 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.61 (3H, s),1.73 (2H, s), 1.91 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.79 (3H, s),3.89 (1H, d, J=15.6 Hz), 4.00 (1H, d, J=15.6 Hz), 4.55 (1H, d, J=13.5Hz), 4.83 (1H, d, J=13.5 Hz), 6.63 (1H, s), 6.89 (2H, d, J=7.8 Hz), 7.07(2H, d, J=7.8 Hz), 7.11-7.20 (5H, m).

REFERENCE EXAMPLE 333N-(3-(4-Isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide

Using (3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)amine obtainedin Reference Example 300, the title compound was synthesized in the samemanner as in Example 63. Yield 94%. Melting point: 181-182° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 2.10 (3H, s),2.25 (3H, s), 2.27 (2H, s), 2.83 (1H, septet, J=6.9 Hz), 3.78 (3H, s),4.00 (2H, s), 6.55 (1H, br s), 6.67 (1H, s), 7.01 (2H, d, J=8.1 Hz),7.06 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 334(7-(1-(4-Isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)amine

To a solution of tert-butyl(7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 223 (306 mg, 0.72 mmol) in ethyl acetate (5 mL) wasadded dropwise a solution of 4 N hydrochloric acid-ethyl acetate (5 mL)under ice-cooling, and the reaction solution was stirred for 30 minutes.The reaction solution was added to a saturated sodium hydrogen carbonatesolution, which was extracted with ethyl acetate. The combined organiclayer was washed with a saturated sodium hydrogen carbonate solution anda saturated brine, dried over anhydrous sodium sulfate, filtered andthen concentrated under reduced pressure to obtain 221 mg (yield:quantitative) of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.97 (3H, s), 2.16 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.14 (2H, t, J=8.4 Hz), 3.34 (2H, br s),4.44 (2H, t, J=8.4 Hz), 5.14 (1H, s), 5.94 (1H, s), 7.10 (2H, d, J=8.1Hz), 7.25 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 335N-(3-(4-Isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide

To a solution ofN-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamideobtained in Reference Example 333 (1.99 g, 5.21 mmol) in dichloromethane(25 mL) was added dropwise boron tribromide

(a 1.0 M dichloromethane solution, 10.4 mL, 10.4 mmol) under argonatmosphere at −78° C., and the mixture was stirred for 30 minutes. Thereaction solution was warmed to room temperature and was stirred for 14hours. The reaction solution was added to a saturated sodium hydrogencarbonate solution to separate the organic layer, and then the aqueouslayer was extracted with ethyl acetate. The entire organic layer waswashed with a saturated brine, dried over anhydrous sodium sulfate,filtered and then concentrated under reduced pressure to obtain 1.83 g(yield 97%) of the oily title compound. Melting point: 202-203° C.(ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.19 (6H, d, J=6.9 Hz), 2.11 (3H, s),2.12 (3H, s), 2.29 (2H, s), 2.82 (1H, septet, J=6.9 Hz), 3.93 (2H, s),6.34 (1H, s), 6.37 (1H, br), 6.62 (1H, s), 7.06 (4H, s).

REFERENCE EXAMPLE 336N-Benzyl-N-(3-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide

UsingN-benzyl-N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamideobtained in Reference Example 332, the title compound was synthesized inthe same manner as in Reference Example 335. Yield 83%. Melting point:167-168° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.66 (3H, s),1.80 (2H, s), 1.87 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.90 (1H, d,J=16.2 Hz), 3.97 (1H, d, J=16.2 Hz), 4.54 (1H, d, J=13.5 Hz), 4.57 (1H,d, J=13.5 Hz), 4.98 (1H, br), 6.59 (1H, s), 6.94 (2H, d, J=7.8 Hz), 7.11(2H, d, J=7.8 Hz), 7.10-7.16 (5H, m).

REFERENCE EXAMPLE 337N-Benzyl-N-(3-bromo-5-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide

UsingN-benzyl-N-(3-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamideobtained in Reference Example 336, the title compound was synthesized inthe same manner as in Reference Example 66. Yield 98%. Melting point:107-108° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.66 (3H, s),1.76 (2H, s), 2.00 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 3.96 (1H, d,J=15.6 Hz), 4.08 (1H, d, J=15.6 Hz), 4.49 (1H, d, J=13.5 Hz), 4.87 (1H,d, J=13.5 Hz), 5.76 (1H, s), 6.93 (2H, d, J=8.4 Hz), 7.09-7.21 (7H, m).

REFERENCE EXAMPLE 338N-Benzyl-N-(3-bromo-4-(2-chloroethoxy)-5-(4-isopropylbenzyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

UsingN-benzyl-N-(3-bromo-5-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamideobtained in Reference Example 337, the title compound was synthesized inthe same manner as in Reference Example 217. Yield 87%. Oily matter.

¹H-NMR (CDCl₃) δ: 0.98 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.54 (3H, s),1.73 (2H, s), 2.07 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.75 (2H, t,J=6.0 Hz), 3.99-4.13 (4H, m), 4.42 (1H, d, J=13.5 Hz), 4.96 (1H, d,J=13.5 Hz), 6.84 (2H, d, J=8.1 Hz), 7.00-7.20 (7H, m).

REFERENCE EXAMPLE 339N-(3-(4-Isopropylbenzyl)-2,6-dimethyl-4-((2-methylprop-2-en-1-yl)oxy)phenyl)-3,3-dimethylbutanamide

To a mixed solution ofN-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethyl)-amino-2-(4-isopropylbenzyl)-1-hydroxy-3,5-dimethylphenyl)-3,3-dimethylbutanamideobtained in Reference Example 335 (300 mg, 0.82 mmol), methallylchloride (89 mg, 0.98 mmol) and potassium carbonate (135 mg, 0.98 mmol)in DMF (5 mL) was stirred at 80° C. for 18 hours under argon atmosphere.Water was added to the reaction solution, which was extracted with ethylacetate. The combined organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, filtered and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain280 mg (yield 81%) of the title compound. Melting point: 129-130° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.19 (6H, d, J=6.9 Hz), 1.72 (3H, s),2.12 (3H, s), 2.22 (3H, s), 2.26 (2H, s), 2.82 (1H, septet, J=6.9 Hz),4.03 (2H, s), 4.38 (2H, s), 4.90 (1H, s), 5.02 (1H, s), 6.53 (1H, s),6.63 (1H, br), 7.04 (4H, s).

REFERENCE EXAMPLE 340N-(4-(Allyloxy)-3-bromo-5-(4-isopropylbenzyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamideobtained in Reference Example 335,N-(3-bromo-5-(4-isopropylbenzyl)-4-hydroxy-2,6-dimethylphenyl)-3,3-dimethylbutanamidewas synthesized in the same manner as in Reference Example 66. Usingthis compound, the title compound was synthesized in the same manner asin Reference Example 213. Yield 33%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.20 (6H, d, J=6.9 Hz), 2.06 (3H, s),2.28 (2H, s), 2.37 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 4.08 (2H, brs), 4.29 (2H, br s), 5.20 (1H, d, J=10.5 Hz), 5.28-5.36 (1H, m),5.98-6.20 (1H, m), 6.65 (1H, s), 7.00 (2H, d, J=8.1 Hz), 7.08 (2H, d,J=8.1 Hz).

REFERENCE EXAMPLE 341N-(4-Hydroxy-3-(4-isopropylbenzyl)-2,6-dimethyl-5-(2-methylprop-2-en-1-yl)phenyl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylbenzyl)-2,6-dimethyl-4-((2-methylprop-2-en-1-yl)oxy)phenyl)-3,3-dimethylbutanamideobtained in Reference Example 339, the title compound was synthesized inthe same manner as in Reference Example 215.

Yield 93%. Melting point: 124-125° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.78 (3H, s),2.15 (3H, s), 2.16 (3H, s), 2.29 (2H, s), 2.84 (1H, septet, J=6.9 Hz),3.38 (2H, s), 4.03 (2H, br s), 4.65 (1H, s), 4.84 (1H, s), 5.05 (1H, s),6.60 (1H, s), 7.04 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 3423,3-Dimethyl-N-(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using 5-amino-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3-(2H)-oneobtained in Reference Example 55, the title compound was synthesized inthe same manner as in Example 1. Yield 91%. Melting point: 181-182° C.(THF-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.42 (6H, s), 2.30-2.32 (5H, m), 2.49(3H, s), 6.55 (1H, br s), 6.79 (1H, s).

REFERENCE EXAMPLE 3433,3-Dimethyl-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-yl)butanamide

Using 3-(4-isopropylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amineobtained in Reference Example 305, the title compound was synthesized inthe same manner as in Example 63. Yield 50%. Melting point: 229-230° C.(THF-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.30 (6H, d, J=6.9 Hz), 2.11 (3H, s),2.27 (3H, s), 2.31 (2H, s), 2.45 (3H, s), 2.96 (1H, septet, J=6.9 Hz),6.67 (1H, br s), 7.24 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 7.48(1H, s).

REFERENCE EXAMPLE 3447-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine

N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 203 (808 mg, 2.3 mmol) was added to a solution ofmethanol (10 mL) and concentrated hydrochloric acid (5 mL), and themixture was heated under reflux for 2 hours. The reaction solution wascooled to room temperature and was poured into a cold sodium bicarbonatesolution, which was extracted with ethyl acetate. The extract was washedwith a saturated brine, dried over sodium sulfate and then concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (hexane ethyl acetate=1:1) to obtain the title compoundas an oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.87 (3H, s), 2.18 (3H, s),2.60 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 3.34 (2H, br), 4.36-4.43 (1H,m), 4.48-4.56 (1H, m), 4.76-4.85 (1H, m), 7.03 (2H, d, J=8.1 Hz), 7.12(2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 345 2-Bromo-1-(4-isopropylphenyl)propan-1-one

Using 2-bromopropanoyl chloride, the title compound was synthesized inthe same manner as in Reference Example 164. Yield 97%. Oily matter.

¹H-NMR (200 MHz, CDCl₃) δ: 1.28 (6H, d, J=7.0 Hz), 1.90 (3H, d, J=7.0Hz), 2.98 (1H, septet, J=7.0 Hz), 5.28 (1H, q, J=7.0 Hz), 7.34 (2H, d,J=8.0 Hz), 7.97 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 3461-(4-Isopropylphenyl)-2-(2,3,5-trimethylphenoxy)propan-1-one

Using 2-bromo-1-(4-isopropylphenyl)propan-1-one obtained in ReferenceExample 345 and 2,3,5-trimethylphenol, the title compound wassynthesized in the same manner as in Reference Example 159. Yield:quantitative. Oily matter.

¹H-NMR (CDCl₃) δ: 1.26 (6H, d, J=7.0 Hz), 1.69 (3H, d, J=7.0 Hz), 2.16(3H, s), 2.19 (3H, s), 2.21 (3H, s), 2.95 (1H, septet, J=7.0 Hz), 5.37(1H, q, J=7.0 Hz), 6.40 (1H, s), 6.59 (1H, s), 7.29-7.32 (2H, m),8.00-8.04 (2H, m).

REFERENCE EXAMPLE 3473-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran

A mixed solution of1-(4-isopropylphenyl)-2-(2,3,5-trimethylphenoxy)propan-1-one obtained inReference Example 346 (61.3 g, 194 mmol), Amberlyst 15 (61.0 g) and amolecular sieve MS 4A (30 g) in toluene (200 mL) was heated under refluxat 80° C. for 2 hours. The reaction solution was filtered throughcelite, and the filtrate was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate:hexane 1:100) to obtain 54.4 g (yield 96%) of the titlecompound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.30 (6H, d, J=7.0 Hz), 2.06 (3H, s), 2.32 (3H, s),2.34 (3H, s), 2.41 (3H, s), 2.96 (1H, septet, J=7.0 Hz), 6.75 (1H, s),7.25 (4H, s).

REFERENCE EXAMPLE 348 3-(4-Isopropylphenyl)-2,6,7-trimethyl-1-benzofuran

Using 2-bromo-1-(4-isopropylphenyl)propan-1-one obtained in ReferenceExample 345 and 2,3-dimethylphenol,1-(4-isopropylphenyl)-2-(2,3-dimethylphenoxy)propan-1-one was obtainedin the same manner as in Reference Example 159. Using this compound, thetitle compound was obtained in the same manner as in Reference Example143. Yield 81%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.31 (6H, d, J=7.0 Hz), 2.38 (3H, s), 2.44 (3H, s),2.53 (3H, s), 2.97 (1H, septet, J=7.0 Hz), 7.02 (1H, d, J=8.0 Hz),7.29-7.45 (5H, m).

REFERENCE EXAMPLE 349(cis)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran

Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran obtained inReference Example 347, the title compound was synthesized in the samemanner as in Reference Example 144. Yield 63%. Melting point: 79-80° C.(methanol).

¹H-NMR (CDCl₃) δ: 1.09 (3H, d, J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 1.90(3H, s), 2.16 (3H, s), 2.24 (3H, s), 2.85 (1H, septet, J=7.0 Hz), 4.30(1H, d, J=7.0 Hz), 4.91-5.05 (1H, m), 6.49 (1H, s), 6.83 (2H, d, J=8.0Hz), 7.08 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 350(cis)-N-Benzyl-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine

Using 3-(4-isopropylphenyl)-2,6,7-trimethyl-1-benzofuran obtained inReference Example 348,3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran wassynthesized in the same manner as in Reference Example 144. Using thiscompound,5-bromo-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuranwas obtained in the same manner as in Reference Example 23. Using thiscompound, the title compound was synthesized in the same manner as inReference Example 24.

Yield 22%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.00 (3H, d, J=7.0 Hz), 1.23 (6H, d, J=7.0 Hz), 2.10(3H, s), 2.24 (3H, s), 2.87 (1H, septet, J=7.0 Hz), 3.44 (1H, br s),4.19 (2H, s), 4.44 (1H, d, J=8.0 Hz), 4.90-4.99 (1H, m), 6.37 (1H, s),6.90 (2H, d, J=8.0 Hz), 7.10 (2H, d, J=8.0 Hz), 7.23-7.36 (5H, m).

REFERENCE EXAMPLE 351(cis)-3-(4-Isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride

Using(cis)-N-benzyl-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 350, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 96%. Melting point:189-190° C. (diisopropyl ether-hexane).

¹H-NMR (CDCl₃) δ: 1.02 (3H, d, J=6.0 Hz), 1.22 (6H, d, J=7.0 Hz), 2.09(3H, s), 2.21 (3H, s), 2.86 (1H, septet, J=7.0 Hz), 3.23 (3H, br), 4.39(1H, d, J=8.0 Hz), 4.89-4.99 (1H, m), 6.36 (1H, s), 6.90 (2H, d, J=8.0Hz), 7.11 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 352(cis)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine

Using(cis)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 349,(cis)-5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuranwas synthesized in the same manner as in Reference Example 23. Usingthis compound,(cis)-N-benzyl-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminewere synthesized in the same manner as in Reference Example 24. Usingthis compound, the title compound was synthesized in the same manner asin Reference Example 30. Yield 83%. Melting point: 91-92° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.06 (3H, d, J=7.0 Hz), 1.21 (6H, d, J=7.0 Hz), 1.84(3H, s), 2.12 (3H, s), 2.21 (3H, s), 2.85 (1H, septet, J=7.0 Hz), 3.25(2H, br s), 4.29 (1H, d, J=8.0 Hz), 4.83-4.96 (1H, m), 6.83 (2H, d,J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 353 2-(3,5-Dimethylphenoxy)-1-phenylethanone

Using 3,5-dimethylphenol and phenacyl bromide, the title compound wassynthesized in the same manner as in Reference Example 177. Yield 86%.Melting point: 104-105° C. (methanol).

¹H-NMR (CDCl₃) δ: 2.28 (6H, s), 5.23 (2H, s), 6.58 (2H, s), 6.63 (1H,s), 7.46-7.54 (2H, m), 7.58-7.65 (1H, m), 7.98-8.04 (2H, m).

REFERENCE EXAMPLE 354 4,6-Dimethyl-3-phenyl-1-benzofuran

Using 2-(3,5-dimethylphenoxy)-1-phenylethanone obtained in ReferenceExample 353, the title compound was synthesized in the same manner as inReference Example 143. Yield: quantitative. Oily matter.

¹H-NMR (CDCl₃) δ: 2.21 (3H, s), 2.43 (3H, s), 6.83 (1H, s), 7.17 (1H,s), 7.38-7.50 (6H, m).

REFERENCE EXAMPLE 355 4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran

Using 4,6-dimethyl-3-phenyl-1-benzofuran obtained in Reference Example354, the title compound was synthesized in the same manner as inReference Example 199. Yield 91%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.91 (3H, s), 2.29 (3H, s), 4.41 (1H, dd, J=8.4, 4.8Hz), 4.51 (1H, dd, J=9.0, 5.1 Hz), 4.85 (1H, d, J=9.0 Hz), 6.48 (1H, s),6.57 (1H, s), 7.11-7.31 (5H, m).

REFERENCE EXAMPLE 3565-Bromo-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran

Using 4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran obtained inReference Example 355, the title compound was synthesized in the samemanner as in Reference Example 23.

Yield 78%. Melting point: 135-136° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 2.04 (3H, s), 2.39 (3H, s), 4.41 (1H, dd, J=9.0, 4.5Hz), 4.56 (1H, dd, J=9.3, 4.2 Hz), 4.85 (1H, d, J=9.0 Hz), 6.67 (1H, s),7.07-7.25 (2H, m), 7.19-7.32 (3H, m).

REFERENCE EXAMPLE 357N-Benzyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine

Using 5-bromo-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran obtained inReference Example 356, the title compound was synthesized in the samemanner as in Reference Example 24. Yield 72%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.89 (3H, s), 2.26 (3H, s), 2.87 (1H, br s), 3.92 (2H,s), 4.37 (1H, dd, J=8.4, 4.8 Hz), 4.52 (1H, dd, J=9.0, 4.2 Hz), 4.82(1H, d, J=9.0 Hz), 6.60 (1H, s), 7.05-7.40 (10H, m).

REFERENCE EXAMPLE 3584,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine

Using N-benzyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 357, the title compound was synthesized inthe same manner as in Reference Example 30. Yield 84%. Melting point:127-128° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.84 (3H, s), 2.19 (3H, s), 3.26 (2H, br s), 4.33 (1H,dd, J=8.7, 4.5 Hz), 4.53 (1H, dd, J=9.0, 4.5 Hz), 4.78 (1H, dd, J=9.0,8.7 Hz), 6.56 (1H, s), 7.09-7.29 (5H, m).

REFERENCE EXAMPLE 359(+)-N-((3R)-2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-2-(4-(trifluoromethyl)phenyl)acetamide

To a DMF solution of(3R)-(+)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 134 (0.89 g, 3 mmol), were addedtriethylamine (0.84 mL, 6 mmol), (4-trifluoromethyl)phenylacetic acid(0.67 g, 3.3 mmol) and diethyl phosphorocyanidate (0.46 mL, 3.3 mmol) at0° C., and the mixture was warmed to room temperature. After stirring atthe same temperature for 1 hour, the reaction solution was poured intocold water (50 mL). The precipitated crystals were taken, and thecrystals were dissolved in ethyl acetate again. The organic layer waswashed with a saturated sodium hydrogen carbonate solution and asaturated brine, and then dried over anhydrous sodium sulfate. Thesolvent was dried under reduced pressure, and the residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain1.19 g (yield 83%) of the title compound. Melting point: 187-189° C.(diethyl ether-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.47 (3H, s), 1.65 (3H, s), 2.04 (3H,s), 2.13 (3H, s), 2.29 (3H, s), 3.79 (2H, s), 4.06 (1H, s), 6.44 (1H,br), 7.02 (4H, br), 7.49 (2H, d, J=8.2 Hz), 7.62 (2H, d, J=8.2 Hz).

REFERENCE EXAMPLE 360(+)-2-(4-Methoxyphenyl)-N-((3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)acetamide

Using(+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 134 and -4-methoxyphenylacetic acid, thetitle compound was synthesized in the same manner as in ReferenceExample 359. Yield 74%. Melting point: 186-188° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.46 (3H, s), 1.64 (3H, s), 2.04 (3H,s), 2.13 (3H, s), 2.28 (3H, s), 3.68 (2H, s), 3.80 (3H, s), 4.06 (1H,s), 6.44 (1H, br), 6.89 (2H, d, J=8.6 Hz), 7.02 (4H, br), 7.25 (2H, d,J=8.6 Hz).

REFERENCE EXAMPLE 361(+)-3-(4-Methoxyphenyl)-N-((3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)propionamide

Using(+)-(3R)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 134 and -4-methoxyphenylpropionic acid,the title compound was synthesized in the same manner as in ReferenceExample 359. Yield 21%. Melting point: 170-172° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.48 (3H, s), 1.63 (3H, s), 1.99 (3H,s), 2.13 (3H, s), 2.29 (3H, s), 2.64 (2H, d, J=7.4 Hz), 2.99 (2H, d,J=7.4 Hz), 3.76 (3H, s), 4.08 (1H, s), 6.44 (1H, br), 6.81 (2H, d, J=8.5Hz), 7.02 (4H, br), 7.16 (2H, d, J=8.5 Hz).

REFERENCE EXAMPLE 3623-(4-Methoxyphenyl)-N-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)propionamide

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 130 and 4-methoxyphenylpropionic acid, thetitle compound was synthesized in the same manner as in ReferenceExample 359. Yield 29%. Melting point: 180-183° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.48 (3H, s), 1.63 (3H, s), 1.99 (3H,s), 2.13 (3H, s), 2.29 (3H, s), 2.64 (2H, d, J=7.3 Hz), 2.99 (2H, d,J=7.3 Hz), 3.76 (3H, s), 4.08 (1H, s), 6.45 (1H, br), 6.81 (2H, d, J=8.5Hz), 7.02 (4H, br), 7.16 (2H, d, J=8.5 Hz).

REFERENCE EXAMPLE 3632-(4-Methoxyphenyl)-N-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)acetamide

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 130 and 4-methoxyphenylacetic acid, thetitle compound was synthesized in the same manner as in ReferenceExample 359. Yield 62%. Melting point: 166-167° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.46 (3H, s), 1.63 (3H, s), 2.03 (3H,s), 2.12 (3H, s), 2.28 (3H, s), 3.68 (2H, s), 3.79 (3H, s), 4.05 (1H,s), 6.43 (1H, br), 6.87 (2H, d, J=8.6 Hz), 7.00 (4H, br), 7.25 (2H, d,J=8.6 Hz).

REFERENCE EXAMPLE 3644-(4-Methoxyphenyl)-N-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 130 and 4-(4-methoxyphenyl)butanoic acid,the title compound was synthesized in the same manner as in ReferenceExample 359. Yield 11%. Melting point: 166-167° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.46 (3H, s), 1.63 (3H, s), 2.03 (3H,s), 2.12 (3H, s), 2.28 (3H, s), 3.68 (2H, s), 3.79 (3H, s), 4.05 (1H,s), 6.43 (1H, br), 6.87 (2H, d, J=8.6 Hz), 7.00 (4H, br), 7.25 (2H, d,J=8.6 Hz).

REFERENCE EXAMPLE 365N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methoxyphenylacetamide

Using3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 120 and 4-methoxyphenylacetyl chloride,the title compound was synthesized in the same manner as in ReferenceExample 63. Yield 74%. Melting point: 171-173° C. (methanol).

¹H-NMR (CDCl₃) δ: 0.98 (3H, s), 1.20 (6H, d, J=6.6 Hz), 1.46 (3H, s),1.64 (3H, s), 2.03 (3H, s), 2.12 (3H, s), 2.84 (1H, septet, J=6.6 Hz),3.68 (2H, s), 3.80 (3H, s), 4.06 (1H, s), 6.45 (1H, br), 6.6-6.9 (2H,m), 6.89 (2H, d, J=8.6 Hz), 7.05 (2H, d, J=8.0 Hz), 7.26 (d, 2H, J=8.6Hz).

REFERENCE EXAMPLE 366N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxyphenyl)propionamide

Using3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 120 and 4-methoxyphenylpropionyl chloride,the title compound was synthesized in the same manner as in ReferenceExample 63. Yield 72%. Melting point: 188-191° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.99-1.01 (3H, m), 1.19-1.26 (6H, m), 1.48 (3H, s),1.64-1.68 (3H, m), 1.99 (3H, s), 2.05-2.13 (5H, m), 2.65-3.04 (3H, m),3.72-3.77 (3H, m), 4.08 (1H, s), 6.47-7.19 (9H, m).

REFERENCE EXAMPLE 367N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-N-(2-(4-methoxyphenyl)ethyl)acetamide

To a suspension of aluminum chloride (1.23 g, 9.25 mmol) in THF (40 mL)was slowly added lithium aluminium hydride (354 mg, 9.31 mmol) withice-cooling, and the mixture was stirred at the same temperature for 10minutes. To this mixture was addedN-(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methoxyphenylacetamideobtained in Reference Example 365 (536 mg, 1.14 mmol), and the mixturewas heated under reflux for 3 hours. The reaction mixture was added toice-water, and the mixture was neutralized with a 8 N aqueous sodiumhydroxide solution. Thereafter, the product was twice extracted withethyl acetate, and the combined organic layer was washed with water,dried over magnesium sulfate, filtered and then concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to obtain3-(4-isopropylphenyl)-N-(2-(4-methoxyphenyl)ethyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine.This compound (537.9 mg, 1.18 mmol) was added to a suspension of sodiumhydride (a 60% paraffin dispersion, 232.1 mg, 5.80 mmol) in DMF (25 mL)at 60° C., and the mixture was stirred for 20 minutes. Acetyl chloride(0.5 mL, 7.03 mmol) was added thereto, and the mixture was stirred atthe same temperature for 1 hour. The reaction mixture was cooled to roomtemperature, and a saturated sodium hydrogen carbonate solution wasadded to the mixture, which was twice extracted with ethyl acetate. Theextract was washed with water, dried over magnesium sulfate, filteredand then concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=3:1) to obtainthe rotational isomer of the object compound (Rf=0.38; hexane:ethylacetate=3:1) (yield 43%). Melting point: 134-136° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.03 (3H, s), 1.22 (6H, d, J=7.0 Hz), 1.54 (3H, s),1.66 (3H, s), 1.72 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.77-2.89 (3H,m), 3.59-3.70 (2H, m), 3.77 (3H, s), 4.11 (1H, s), 6.77-7.13 (8H, m).

REFERENCE EXAMPLE 368N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-N-(2-(4-methoxyphenyl)ethyl)acetamide

The residue, as operated in the same manner as in Reference Example 367,was purified by silica gel column chromatography (hexane:ethylacetate=3:1) to obtain the rotational isomer of the object compound(Rf=0.25; hexane:ethyl acetate=3:1) (yield 34%). Amorphous matter.

¹H-NMR (CDCl₃) δ: 1.03 (3H, s), 1.23 (6H, d, J=6.8 Hz), 1.53 (3H, s),1.73 (3H, s), 1.75 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.67-2.75 (2H,m), 2.80-2.94 (1H, septet, J=6.8 Hz), 3.57-3.74 (2H, m), 3.77 (3H, s),4.14 (1H, s), 6.77-7.13 (8H, m).

EXAMPLE 1N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(430 mg, 1.46 mmol) obtained in Reference Example 30 andtert-butylacetyl chloride (0.22 mL, 1.53 mmol) in dichloromethane (10mL) was added triethylamine (0.22 mL, 1.61 mmol) at room temperature,and the reaction mixture was stirred at room temperature for 1 hour.Water was added to the reaction solution, the organic layer wasseparated, and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with 1 N hydrochloric acid and anaqueous saturated sodium hydrogen carbonate solution, dried overmagnesium sulfate, filtered, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=8:1) to obtain 400 mg (yield: 70%)of the title compound. Melting point: 171-173° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.81 (3H, s),2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J=6.9 Hz),4.41 (1H, dd, J=8.7, 4.8 Hz), 4.52 (1H, dd, J=8.7, 4.8 Hz), 4.82 (1H, t,J=8.7 Hz), 6.49 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.4Hz).

EXAMPLE 2N-(3-(4-Isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 31, the title compound was synthesized inthe same manner as in Example 1. Yield: 54%. Melting point: 177-178° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.09 (9H, s), 1.24 (6H, d, J=7.2 Hz), 2.13 (3H, s),2.18 (2H, s), 2.20 (3H, s), 2.87 (1H, septet, J=7.2 Hz), 4.28 (1H, dd,J=9.0, 7.5 Hz), 4.56-4.63 (1H, m), 4.84 (1H, t, J=9.0 Hz), 6.69 (1H, brs), 6.94 (1H, s), 7.11 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz).

EXAMPLE 3N-(3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 32, the title compound was synthesized inthe same manner as in Example 1. Yield: 67%. Melting point: 130-131° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.21 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 4.40 (1H, dd,J=8.4, 4.8 Hz), 4.49 (1H, dd, J=9.0, 4.8 Hz), 4.77-4.85 (1H, m), 6.48(1H, br s), 6.62 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1Hz).

EXAMPLE 4N-(3-(4-Isopropylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 3-(4-isopropylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained inReference Example 33, the title compound was synthesized in the samemanner as in Example 1.

Yield: 71%. Melting point: 119-120° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.23 (6H, d, J=6.9 Hz), 2.13 (2H, s),2.88 (1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=9.0, 7.5 Hz), 4.56-4.64(1H, m), 4.87 (1H, t, J=9.0 Hz), 6.79 (1H, d, J=8.7 Hz), 6.89 (1H, brs), 7.08-7.23 (6H, m)

EXAMPLE 5N-(3-(4-Isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 34, the title compound was synthesized inthe same manner as in Example 1. Yield: 37%. Melting point: 194-195° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.72 (3H, s),1.74 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.87 (1H,septet, J=6.9 Hz), 4.37 (1H, d, J=8.4 Hz), 4.42 (1H, d, J=8.4 Hz), 6.48(1H, br s), 7.13 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz).

EXAMPLE 6N-(3-(4-Isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 35, the title compound was synthesized inthe same manner as in Example 1. Yield: 59%. Melting point: 132-133° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.71 (3H, s),2.14 (3H, s), 2.19 (3H, s), 2.20 (2H, s), 2.86 (1H, septet, J=6.9 Hz),4.40 (1H, d, J=8.7 Hz), 4.57 (1H, d, J=8.7 Hz), 6.72 (1H, br s), 6.97(1H, s), 7.13 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz).

EXAMPLE 7(+)-N-((3R)-3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 1 was separated using high performance liquidchromatography (apparatus: GIGAPREP SK-1 manufactured by Shiseido Co.,Ltd., Column: CHIRALCEL OD (50 (i, d)×500 mm) manufactured by DaicelChemical Industries, Ltd.), Mobile phase: hexane:ethanol=95:5, Flowrate: 60 mL/min, Column temperature: 35° C., Sample injection amount: 30mg/times, Detect: UV 220 nm), and a shorter retention time was obtainedas the title compound. Recovery: 44%. Melting point: 186-187° C. (ethylacetate-hexane). [α]_(D) ²⁰=+64.0° (c=0.44, chloroform).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.84 (3H, s),2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.85 (1H, septet, J=6.9 Hz),4.40 (1H, dd, J=8.7, 4.8 Hz), 4.51 (1H, dd, J=9.3, 4.8 Hz), 4.81 (1H, t,J=9.0 Hz), 6.47 (1H, br s), 7.03 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4Hz).

EXAMPLE 8(−)-N-((3S)-3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 1 was separated using high performance liquidchromatography (apparatus: GIGAPREP SK-1 manufactured by Shiseido Co.,Ltd., Column: CHIRALCEL OD (50 (i, d)×500 mm) manufactured by DaicelChemical Industries, Ltd.),

Mobile phase: hexane:ethanol=95:5, Flow rate: 60 mL/min, Columntemperature: 35° C., Sample injection amount: 30 mg/times, Detect: UV220 nm), and a longer retention time was obtained as the title compound.Recovery: 42%. Melting point: 185-186° C. (ethyl acetate-hexane).[α]_(D) ²⁰=−61.2° (c=0.42, chloroform).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.84 (3H, s),2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.85 (1H, septet, J=6.9 Hz),4.40 (1H, dd, J=8.7, 4.8 Hz), 4.51 (1H, dd, J=9.0, 4.8 Hz), 4.81 (1H, t,J=8.7 Hz), 6.49 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1Hz).

EXAMPLE 9N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)propionamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and propionyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 74%.Melting point: 164-165° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.00-1.37 (9H, m), 1.82 (3H, s), 2.09-2.45 (8H, m),2.85 (1H, septet, J=6.9 Hz), 4.37-4.60 (2H, m), 4.77-4.89 (1H, m), 6.54(1H, br s), 6.99-7.19 (4H, m)

EXAMPLE 10N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and butyryl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 80%.Melting point: 177-178° C. (THF-diisopropyl ether).

¹H-NMR (CDCl₃) δ: 1.02 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz),1.71-1.87 (5H, m), 2.13 (3H, s), 2.18 (3H, s), 2.35 (2H, t, J=7.5 Hz),2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd, J=9.0, 4.5 Hz), 4.53 (1H, dd,J=9.0, 4.5 Hz), 4.83 (1H, t, J=9.0 Hz), 6.54 (1H, br s), 6.99-7.06 (2H,m), 7.11-7.15 (2H, m).

EXAMPLE 11N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)pentanamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and pentanoyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 72%.Melting point: 128-129° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.72-1.00 (3H, m), 1.21 (6H, d, J=6.9 Hz), 1.36-1.90(7H, m), 2.11-2.42 (8H, m), 2.85 (1H, septet, J=6.9 Hz), 4.37-4.59 (2H,m), 4.77-4.89 (1H, m), 6.53 (1H, br s), 6.99-7.17 (4H, m).

EXAMPLE 12N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-(4-methoxyphenyl)acetamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and (4-methoxyphenyl)acetyl chloride,the title compound was synthesized in the same manner as in Example 1.Yield: 62%. Melting point: 166-167° C. (Methanol).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.72 (3H, s), 2.02 (3H, s),2.14 (3H, s), 2.83 (1H, septet, J=6.9 Hz), 3.69 (2H, s), 3.80 (3H, s),4.39 (1H, dd, J=9.0, 4.5 Hz), 4.48 (1H, dd, J=9.0, 4.5 Hz), 4.80 (1H, t,J=9.0 Hz), 6.46 (1H, br s), 6.90 (2H, d, J=8.4 Hz), 7.01 (2H, d, J=8.4Hz), 7.13 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz).

EXAMPLE 13N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxyphenyl)propionamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and 3-(4-methoxyphenyl)propionylchloride, the title compound was synthesized in the same manner as inExample 1.

Yield: 83%. Melting point: 119-120° C. (ethyl acetate-hexane).

1H-NMR (CDCl₃) δ: 1.21 (6H, d, J=7.2 Hz), 1.66-1.75 (3H, m), 1.97-2.20(6H, m), 2.61-3.02 (5H, m), 3.71-3.78 (3H, m), 4.35-4.56 (2H, m),4.77-4.85 (1H, m), 6.45 (1H, br s), 6.62-7.20 (8H, m).

EXAMPLE 14N-(tert-Butyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(300 mg, 1.02 mmol) obtained in Reference Example 30 in dichloromethane(5 mL) was added tert-butyl isocyanate (0.14 mL, 1.22 mmol) and theresulting mixture was refluxed for 20 hours. The reaction solution wasadded to water and the product was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (hexane:ethylacetate=2:1) and recrystallized from THF-hexane to obtain 283 mg (yield:70%) of the title compound. Melting point: 201-202° C.

¹H-NMR (CDCl₃) δ: 1.10-1.40 (15H, m), 1.87 (3H, s), 2.19 (6H, s), 2.86(1H, septet, J=6.9 Hz), 4.00 (1H, br s), 4.45 (1H, dd, J=8.7, 4.5 Hz),4.55 (1H, dd, J=8.7, 4.5 Hz), 4.86 (1H, t, J=8.7 Hz), 5.31 (1H, br s),7.00 (2H, d, J=8.0 Hz), 7.12 (2H, d, J=8.0 Hz).

EXAMPLE 15 Ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and ethyloxalyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 76%.Melting point: 83-84° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.42 (3H, t, J=7.2 Hz), 1.83(3H, s), 2.13 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J=6.9 Hz),4.37-4.46 (3H, m), 4.54 (1H, dd, J=9.0, 4.5 Hz), 4.85 (1H, t, J=9.0 Hz),7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 8.27 (1H, br s).

EXAMPLE 16N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-2-oxobutanamide

To a solution of ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate(100 mg, 0.25 mmol) obtained in Example 15 in THF (3 ml) was addeddropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride(2.0 M THF solution, 0.26 mL, 0.5 mmol) and the mixture was stirred for30 minutes. After the reaction solution was stirred at room temperaturefor 1 hour, the reaction solution was added to ice and the product wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=4:1) and recrystallizedfrom ethyl acetate-hexane to obtain 29 mg (yield: 28%) of the titlecompound. Melting point: 142-143° C.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.37 (9H, s), 1.81 (3H, s),2.10 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd,J=9.0, 4.5 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz), 4.82 (1H, t, J=9.0 Hz),7.03 (2H, d, J=7.8 Hz), 7.12 (2H, d, J=7.8 Hz), 8.00 (1H, br s).

EXAMPLE 17N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxobutanamide

To a solution of 2-oxobutanoic acid (259 mg, 2.54 mmol) in THF (5 mL)was added dropwise with ice-cooling oxalyl chloride (0.33 mL, 3.80 mmol)and added DMF (three drops), and the mixture was stirred for 30 minutes.The reaction solution was warmed to room temperature and stirred at thesame temperature for 1 hour, and then the solvent was distilled offunder reduced pressure. The residue was dissolved in dichloromethane (5mL) and the product was added dropwise with ice-cooling to a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(500 mg, 1.69 mmol) obtained in Reference Example 30 and triethylamine(0.24 mL, 1.69 mmol) in THF (5 mL), and the resulting mixture wasstirred for 30 minutes. After the reaction solution was warmed to roomtemperature, water was added to the reaction solution and the productwas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=2:1) to obtain 363 mg (yield: 57%) of the title compound. Yield:57%. Melting point: 97-98° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=7.2 Hz), 1.22 (6H, d, J=6.9 Hz), 1.79(3H, s), 2.09 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.01(2H, q, J=7.2 Hz), 4.42 (1H, dd, J=9.0, 4.5 Hz), 4.53 (1H, dd, J=9.0,4.5 Hz), 4.83 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=7.8 Hz), 7.12 (2H, d,J=7.8 Hz), 8.13 (1H, s).

EXAMPLE 182-Hydroxy-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a solution ofN-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-oxobutanamideobtained in Example 17 (237 mg, 0.62 mmol) in methanol (5 mL) was addedsodium borohydride (24 mg, 0.62 mmol) at 0° C. and the resulting mixturewas stirred at room temperature for 30 minutes. Water was added to thereaction solution and the product was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to obtain 170 mg(yield: 72%) of the title compound. Melting point: 146-147° C.

¹H-NMR (CDCl₃) δ: 1.06 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz),1.70-1.88 (4H, m), 1.88-2.05 (1H, m), 2.12 (3H, s), 2.18 (3H, s),2.50-2.60 (2H x 0.5, m), 2.86 (1H, septet, J=6.9 Hz), 4.22-4.28 (2H x0.5, m), 4.41 (1H, dd, J=9.0, 4.5 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz),4.82 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=7.5 Hz), 7.11 (2H, d, J=7.5 Hz),7.58 (1H x 0.5, br s), 7.60 (1H x 0.5, br s).

EXAMPLE 192-Hydroxy-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of ethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)oxamate(500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) was addeddropwise at 0° C. under an argon atmosphere tert-butylmagnesium chloride(2.0 M THF solution, 1.9 mL, 3.78 mmol) and the mixture was stirred for30 minutes. After the reaction solution was warmed to room temperatureand was stirred at the same temperature for 1 hour, the reactionsolution was added to ice and the product was extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) and recrystallized from ethyl acetate-hexaneto obtain 194 mg (yield: 38%) of the title compound as a diastereomermixture. Melting point: 165-166° C.

¹H-NMR (CDCl₃) δ: 1.09 (9H, s), 1.20-1.26 (6H, m), 1.84 (3H, s), 2.14(3H, s), 2.18 (3H, s), 2.64 (1H x 0.5, d, J=5.1 Hz), 2.70 (1H x 0.5, d,J=5.1 Hz), 2.80-2.92 (1H, m), 3.91 (1H x 0.5, d, J=5.1 Hz), 3.92 (1H x0.5, d, J=5.1 Hz), 4.41 (1H, dd, J=9.0, 4.5 Hz), 4.52 (1H, dd, J=9.0,4.5 Hz), 4.82 (1H, t, J=9.0 Hz), 7.03 (2H, d, J=7.8 Hz), 7.12 (2H, d,J=7.8 Hz), 7.36 (1H x 0.5, br s), 7.47 (1H x 0.5, br s).

EXAMPLE 20N-(7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(650 mg, 1.71 mmol) obtained in Example 3 and 1,1-dichloromethyl methylether (237 mg, 2.06 mmol) in dichloromethane (5 mL) was added dropwiseat 0° C. under an argon atmosphere and ice-cooling titaniumtetrachloride (0.34 mL, 3.07 mmol), and the mixture was stirred at thesame temperature for 20 minutes. Water was added to the reactionsolution and the product was extracted with dichloromethane. The organiclayer was washed with an aqueous saturated sodium hydrogen carbonatesolution, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain 520 mg (yield: 75%)of the title compound. Melting point: 177-178° C (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.26 (2H, s), 2.51 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.49-4.61 (2H,m), 4.92-5.05 (1H, m), 6.55 (hi, br s), 7.03 (2H, d, J=8.1 Hz), 7.13(2H, d, J=8.1 Hz), 10.4 (1H, s).

EXAMPLE 21N-(7-(Hydroxymethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(370 mg, 0.91 mmol) obtained in Example 20 in methanol (5 mL) was addedsodium borohydride (34 mg, 0.91 mmol) at room temperature and themixture was stirred for 1 hour. The reaction solution was concentratedunder reduced pressure and the residue was extracted with ethyl acetate.The organic layer was washed with water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained residuewas recrystallized from ethyl acetate-hexane to obtain 290 mg (yield:78%) of the title compound. Melting point: 274-275° C.

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.00 (1H, br s), 2.26 (5H, s), 2.86 (1H, septet, J=6.9 Hz), 4.43 (1H,dd, J=8.1, 4.8 Hz), 4.52 (1H, dd, J=9.3, 4.8 Hz), 4.64-4.93 (3H, m),6.54 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 22N-(7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To methylmagnesium bromide (2.0 M THF solution, 5.0 mL, 10.0 mmol) wasaddedN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(780 mg, 1.91 mmol) obtained in Example 20 at 0° C. and the reactionsolution was stirred at the same temperature for 1 hour. The reactionsolution was added to water and the product was extracted with ethylacetate.

The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was recrystallized from hexane-ethyl acetate to obtain590 mg (yield: 73%) of the title compound as a diastereomer mixture.Melting point: 156-157° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.87-1.32 (15H, m), 1.50-1.62 (3H, m), 1.86 (3H, s),2.17-2.25 (5H, s), 2.86 (1H, septet, J=6.9 Hz), 3.42-3.52 (1H, m),4.47-4.52 (2H, m), 4.82-5.09 (2H, m), 6.50 (1H, br s), 7.00-7.05 (2H,m), 7.03-7.15 (2H, m).

EXAMPLE 23N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a mixture ofN-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(200 mg, 0.47 mmol) obtained in Example 22 and trifluoroacetic acid (3mL) was added under ice cooling triethylsilane (0.5 mL, 3.2 mmol) andthe resulting mixture was stirred at room temperature for 30 minutes.After the reaction solution was concentrated under reduced pressure, tothe residue was added an aqueous saturated sodium hydrogen carbonatesolution and the aqueous layer was made alkaline, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=10:1) andrecrystallized from hexane to obtain 100 mg (yield: 52%) of the titlecompound. Melting point: 135-136° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.90-1.25 (18H, m), 1.84 (3H, s), 2.18 (3H, s), 2.24(2H, s), 2.65 (2H, q, J=7.5 Hz), 2.85 (1H, septet, J=6.9 Hz), 4.40 (1H,dd, J=8.7, 4.8 Hz), 4.50 (1H, dd, J=9.0, 4.8 Hz), 4.81 (1H, t, J=9.0Hz), 6.50 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 24N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N,3,3-trimethylbutanamide

To a solution ofN-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(200 mg, 0.51 mmol) synthesized in Example 1 in DMF (3 mL) was addedsodium hydride (a 60% dispersion in liquid paraffin, 24 mg, 0.6 mmol) at0° C. and the resulting mixture was stirred at room temperature for 30minutes. To the reaction solution was added methyl iodide (78 mg, 0.55mmol) and the resulting mixture was stirred at room temperature for 30minutes. Water was added to the reaction solution and the product wasextracted with diisopropyl ether. The extracts were washed with water,dried over magnesium sulfate, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane ethyl acetate=4:1) to obtain 25 mg (yield: 12%)of the desired product having low polarity, of two rotational isomers ofthe title compound. Melting point: 122-123° C. (petroleum ether).

¹H-NMR (CDCl₃) δ: 0.99 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.75 (3H, s),1.79 (2H, s), 2.06 (3H, s), 2.18 (3H, s), 2.87 (H, septet, J=6.9 Hz),3.00 (3H, s), 4.44 (1H, dd, J=8.7, 4.8 Hz), 4.55 (1H, dd, J=9.0, 4.8Hz), 4.87 (1H, t, J=9.0 Hz), 7.02 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1Hz).

EXAMPLE 25N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N,3,3-trimethylbutanamide

By the silica gel column chromatography (hexane ethyl acetate=4:1) inExample 24, 28 mg (yield: 14%) of the title compound having highpolarity of the two rotational isomers was obtained. Melting point:80-82° C. (petroleum ether).

¹H-NMR (CDCl₃) δ: 0.91 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.72 (2H, s),1.73 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J=6.9 Hz),3.06 (3H, s), 4.43 (1H, dd, J=8.7, 4.8 Hz), 4.55 (1H, dd, J=9.0, 4.8Hz), 4.86 (1H, t, J=9.0 Hz), 6.95 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1Hz).

EXAMPLE 26N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(1-pyrrolidinylmethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of pyrrolidine (0.20 mL, 2.4 mmol) in methanol (5 mL) wasadded titanium tetraisopropoxide (0.36 mL, 1.20 mmol) andN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(250 mg; 0.61 mmol) obtained in Example 20 at 0° C. and the resultingmixture was stirred at room temperature for 14 hours. To the reactionsolution was added sodium borohydride (23.2 mg, 0.61 mol) at roomtemperature and the resulting mixture was stirred for 1.5 hours. Waterwas added to the reaction solution and the product was concentratedunder reduced pressure, and the residue was extracted with ethylacetate. The obtained residue was purified by basic silica gel columnchromatography (hexane:ethyl acetate=2:1) to obtain 140 mg (yield: 49%)of the title compound. Amorphous substance.

¹H-NMR (CDCl₃) δ: 1.09 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.62-1.87 (7H,m), 2.22 (2H, s), 2.26 (3H, s), 2.47-2.62 (4H, m), 2.85 (1H, septet,J=6.9 Hz), 3.58 (1H, d, J=12.0 Hz), 3.67 (1H, d, J=12.0 Hz), 4.38 (1H,dd, J=8.4, 4.5 Hz), 4.48 (1H, dd, J=9.0, 4.5 Hz), 4.78 (1H, t, J=9.0Hz), 6.65 (1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 27N-(7-((Dimethylamino)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 20 and dimethylamine, the title compound wassynthesized in the same manner as in Example 26. Yield: 37%. Amorphoussubstance.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.20-2.32 (11H, m), 2.85 (1H, septet, J=6.9 Hz), 3.39 (H, d, J=12.3 Hz),3.45 (1H, d, J=12.3 Hz), 4.40 (1H, dd, J=8.7, 4.8 Hz), 4.51 (1H, dd,J=9.0, 4.8 Hz), 4.80 (1H, t, J=8.7 Hz), 6.51 (1H, br s), 7.01 (2H, d,J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz.

EXAMPLE 28N-(7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To methylmagnesium bromide (2.0 M THF solution, 5.0 mL, 10.0 mmol) wasaddedN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(1.0 g, 1.91 mmol) obtained in Example 20 at 0° C. and the reactionsolution was stirred at the same temperature for 1 hour. The reactionsolution was poured into water and the product was extracted with ethylacetate. The organic layer was washed with water and 1 N hydrochloricacid, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain 192 mg (yield: 19%)of the title compound as a low polarity isomer. Melting point: 147-148°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.51 (3H, d,J=6.6 Hz), 1.86 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 3.51 (1H, d, J=10.5 Hz), 4.43-4.58 (2H, m), 4.82-5.11 (2H,m), 6.51 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 29N-(7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

The residue treated in the same manner as described in the Example 28was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to obtain 122 mg (yield: 12%) of the title compound as ahigh polarity isomer. Melting point: 169-170° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.55 (3H, d,J=6.6 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 3.49 (1H, d, J=9.9 Hz), 4.43-4.58 (2H, m), 4.82-5.12 (2H, m),6.53 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 30N-(7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To ethylmagnesium chloride (2.0 M THF solution, 5.0 mL, 10.0 mmol) wasaddedN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(0.7 g, 1.72 mmol) obtained in Example 20 at 0° C. and the reactionsolution was stirred at the same temperature for 1 hour. The reactionsolution was added to water and the product was extracted with ethylacetate. The organic layer was washed with water and 1 N hydrochloricacid, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain 264 mg (yield: 35%)of the title compound as a low polarity isomer. Melting point: 145-146°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.90-1.05 (3H, m), 1.11 (9H, s), 1.21 (6H, d, J=6.9Hz), 1.69-1.95 (5H, m), 2.17 (3H, s), 2.25 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 3.32 (1H, d, J=10.2 Hz), 4.41-4.57 (2H, m), 4.72-4.90 (2H,m), 6.51 (1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.4 Hz).

EXAMPLE 31N-(7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

The residue treated in the same manner as described in the Example 30was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to obtain 160 mg (yield: 21%) of the title compound as ahigh polarity isomer. Melting point: 165-167° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.87-1.09 (3H, m), 1.11 (9H, s), 1.22 (6H, d, J=6.9Hz), 1.77-1.93 (5H, m), 2.17 (3H, s), 2.24 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 3.36 (1H, d, J=10.2 Hz), 4.40-4.52 (2H, m), 4.72-4.90 (2H,m), 6.56 (1H, br s), 7.01 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz).

EXAMPLE 32N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixture ofN-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(580 mg, 1.37 mmol) obtained in Example 22 and manganese dioxide (1.43g, 16.4 mmol) were stirred at 100° C. for two hours. Insoluble materialswere filtered off, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain 440 mg (yield: 76%)of the title compound. Melting point: 200-201° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.8 Hz), 1.89 (3H, s),2.23 (3H, s), 2.26 (2H, s), 2.58 (3H, s), 2.87 (1H, septet, J=6.8 Hz),4.41-4.58 (2H, m), 4.78-4.96 (1H, m), 6.47 (1H, br s), 7.03 (2H, d,J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz).

EXAMPLE 33N-(7-(1-Hydroxy-1-methylethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 32, the title compound was synthesized in the samemanner as in Example 22. Yield: 34%. Melting point: 133-134° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.8 Hz), 1.68 (3H, s),1.70 (3H, s), 1.86 (3H, s), 2.26 (2H, s), 2.35 (3H, s), 2.86 (1H,septet, J=6.8 Hz), 4.37-4.55 (3H, m), 4.75-4.88 (1H, m), 6.47 (1H, brs), 7.03 (2H, d, J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz).

EXAMPLE 34N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using a diastereo mixture ofN-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in the synthesis in Examples 30 and 31, the title compound wassynthesized in the same manner as in Example 23. Yield: 86%. Meltingpoint: 145-148° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.80-1.35 (18H, m), 1.45-1.65 (2H, m), 1.80 (3H, s),2.17 (3H, s), 2.25 (2H, s), 2.57-2.68 (2H, m), 2.85 (1H, septet, J=6.8Hz), 4.40 (1H, dd, J=8.4, 6.6 Hz), 4.50 (1H, dd, J=8.8, 6.6 Hz), 4.80(1H, t, J=8.4 Hz), 6.49 (1H, br s), 7.04 (2H, d, J=8.4 Hz), 7.12 (2H, d,J=8.4 Hz).

EXAMPLE 35N-(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(1.0 g, 2.63 mmol) obtained in Example 3 in acetonitrile (30 mL) wasadded N-bromosuccinimide (468 mg, 2.63 mmol) at 0° C. and the reactionmixture was stirred at room temperature for 2 hours. Water was added tothe reaction solution, the organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined organic layers werewashed with water, dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The solvent was distilled off underreduced pressure. The obtained residue was recrystallized from ethanolto obtain 1.10 g (yield: 91%) of the title compound. Melting point:191-193° C.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.82 (3H, s),2.24 (2H, s), 2.33 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.51 (1H, dd,J=9.0, 4.8 Hz), 4.63 (1H, dd, J=9.0, 4.8 Hz), 4.93 (1H, t, J=9.3 Hz),6.54 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 36N-(3-(4-Isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixture ofN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(250 mg, 0.545 mmol) obtained in Example 35, copper(I) bromide (78 mg,0.545 mmol), ethyl acetate (88 mg, 1.00 mmol), and 28% sodiummethoxide-methanol solution (20 mL) was refluxed with heating for 6hours. 1 N Hydrochloric acid was added to the reaction solution and theproduct was extracted with diisopropyl ether. The extracts were washedwith water, dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=4:1) and recrystallized fromhexane-ethyl acetate to obtain 130 mg (yield: 58%) of the titlecompound. Melting point: 191-193° C.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.83 (3H, s),2.16 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.89 (3H, s),4.44-4.55 (2H, m), 4.87 (1H, t, J=8.1 Hz), 6.47 (1H, br s), 7.05 (2H, d,J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 37(+)-N-((3R)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(+)-(3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 141, the title compound was synthesized inthe same manner as in Example 1. Yield: 93%. Melting point: 148-149° C.(ethyl acetate-hexane). [α]_(D) ²⁰=+93.2° (c=0.54, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.22 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.41 (1H, dd,J=9.0, 4.8 Hz), 4.50 (1H, dd, J=9.0, 4.8 Hz), 4.83 (1H, t, J=9.0 Hz),6.47 (1H, br s), 6.63 (1H, s), 7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d,J=8.1 Hz).

EXAMPLE 38(+)-N-((3R)-7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(933 mg, 2.46 mmol) obtained in Example 37 in dichloromethane (20 mL)was added aluminum chloride (721 mg, 5.40 mmol) at −70° C. under anargon atmosphere and the mixture was stirred for 20 minutes. To thereaction solution was added dropwise acetyl chloride (424 mg, 5.40 mmol)at the same temperature and the reaction mixture was gradually warmed to10° C. The reaction solution was added to ice, the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water, an aqueous saturatedsodium hydrogen carbonate solution and saturated brine, dried oversodium sulfate, filtered, and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=2:1) to synthesize 873 mg (yield: 84%) of thetitle compound. Melting point: 176-177° C. (ethyl acetate-hexane).[α]_(D) ²⁰=+6.2° (c=0.53, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s),2.22 (3H, s), 2.25 (2H, s), 2.58 (3H, s), 2.86 (1H, septet, J=6.9 Hz),4.46-4.55 (2H, m), 4.89 (1H, t, J=8.4 Hz), 6.53 (1H, br s), 7.03 (2H, d,J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).

EXAMPLE 39(−)-N-((3R)-7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 37, the title compound was synthesized in the samemanner as in Example 20. Yield: 83%. Melting point: 179-180° C. (ethylacetate-hexane). [α]_(D) ²⁰=−25.8° (c=0.48, chloroform).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.23 (2H, s), 2.52 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.45-4.60 (2H,m), 4.97 (1H, t, J=10.8 Hz), 6.49 (1H, br s), 7.03 (2H, d, J=8.1 Hz),7.14 (2H, d, J=8.1 Hz), 10.43 (1H, s)

EXAMPLE 40(+)-N-((3R)-7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A compound, which was produced according to the same manner as inExample 28 using(−)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 39, was purified by silica gel column chromatography(hexane ethyl acetate=4:1) to obtain a low polarity isomer of the titlecompound. Yield: 33%. Melting point: 188-189° C. (ethyl acetate-hexane).[α]_(D) ²⁰=+63.4° (c=0.49, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.52 (3H, d,J=6.6 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 3.50 (1H, br d), 4.45-4.54 (2H, m), 4.85-4.94 (1H, m),5.00-5.10 (1H, m), 6.50 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.12 (2H, d,J=8.1 Hz).

EXAMPLE 41(+)-N-((3R)-7-(1-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A compound, which was produced according to the same manner as inExample 28 using(−)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 39, was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain a high polarity isomer of the titlecompound. Yield: 49%. Melting point: 149-150° C. (ethyl acetate-hexane).[α]_(D) ²⁰=+15.2° (c=0.49, chloroform).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.55 (3H, d,J=6.6 Hz), 1.85 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 3.47 (1H, br d), 4.40-4.55 (2H, m), 4.83-4.91 (1H, m),5.01-5.11 (1H, m), 6.50 (1H, br s), 7.03 (2H, d, J=7.8 Hz), 7.13 (2H, d,J=7.8 Hz).

EXAMPLE 42(+)-N-((3R)-7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution of(+)-N-((3R)-7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(746 mg, 1.77 mmol) obtained in Examples 40 and 41, and 10% palladium oncarbon (water content: 50%, 75 mg) in ethanol (8 mL) was refluxed withheating for 2 hours. The catalyst was removed and the reaction solutionwas concentrated under reduced pressure.

The obtained residue was recrystallized from THF-hexane to obtain 589 mg(yield: 96%) of the title compound. Melting point: 156-157° C. [α]_(D)²⁰+50.7° (c 0.46, chloroform).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.14 (3H, t, J=7.5 Hz), 1.22 (6H, d,J=6.9 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.66 (2H, q, J=7.5Hz), 2.85 (1H, septet, J=6.9 Hz), 4.41 (1H, dd, J=9.0, 4.5 Hz), 4.51(1H, dd, J=9.0, 4.5 Hz), 4.82 (1H, t, J=9.0 Hz), 6.47 (1H, br s), 7.04(2H, d, J=7.8 Hz), 7.12 (2H, d, J=7.8 Hz).

EXAMPLE 43(+)-N-((3R)-7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A compound, which was produced according to the same manner as inExample 30 using(−)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 39, was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain a low polarity isomer of the titlecompound. Yield: 25%. Melting point: 205-206° C. (ethyl acetate-hexane).[α]_(D) ²⁰=+54.80 (c=0.44, chloroform).

¹H-NMR (CDCl₃) δ: 0.99 (3H, t, J=7.5 Hz), 1.11 (9H, s), 1.21 (6H, d,J=6.9 Hz), 1.70-1.93 (5H, m), 2.17 (3H, s), 2.23 (2H, s), 2.86 (1H,septet, J=6.9 Hz), 3.31 (1H, br d), 4.42-4.52 (2H, m), 4.74-4.80 (1H,m), 4.85 (1H, t, J=8.1 Hz), 6.49 (1H, br s), 7.01 (2H, d, J=8.4 Hz),7.11 (2H, d, J=8.4 Hz).

EXAMPLE 44(+)-N-((3R)-7-(1-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A compound, which was produced according to the same manner as inExample 30 using(−)-N-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 39, was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain a high polarity isomer of the titlecompound. Yield: 38%. Amorphous powder. [α]_(D) ²⁰=+16.1° (c=0.54,chloroform).

¹H-NMR (CDCl₃) δ: 1.00 (3H, t, J=7.5 Hz), 1.09 (9H, s), 1.24 (6H, d,J=6.9 Hz), 1.76-1.95 (5H, m), 2.15 (3H, s), 2.23 (2H, s); 2.85 (1H,septet, J=6.9 Hz), 3.41 (1H, br d), 4.41-4.49 (2H, m), 4.73-4.88 (2H,m), 6.85 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 45(+)-N-((3R)-3-(4-Isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution of a diastereo mixture of(+)-N-((3R)-7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(620 mg, 1.42 mmol) obtained in Examples 43 and 44, and 10% palladium oncarbon (water content: 50%, 62 mg) in acetic acid (3 mL) was reacted at80° C. for 2 hours. The catalyst was removed, water was added to thereaction solution, and the product was extracted with ethyl acetate. Theorganic layer was washed with water, an aqueous saturated sodiumhydrogen carbonate solution and saturated brine, dried over sodiumsulfate, filtered, and then concentrated under reduced pressure. Theobtained residue was recrystallized from ethyl acetate-hexane to obtain423 mg (yield: 71%) of the title compound. Melting point: 184-185° C.[α]_(D) ²⁰=+41.6° (c=0.51, chloroform).

¹H-NMR (CDCl₃) δ: 0.98 (3H, t, J=7.5 Hz), 1.12 (9H, s), 1.22 (6H, d,J=6.9 Hz), 1.50-1.60 (2H, m), 1.85 (3H, s), 2.17 (3H, s), 2.25 (2H, s),2.57-2.63 (2H, m), 2.85 (1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=9.0, 4.5Hz), 4.50 (1H, dd, J=9.0, 4.5 Hz), 4.80 (1H, t, J=9.0 Hz), 6.46 (1H, brs), 7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 46(+)-N-((3R)-7-(1-Hydroxy-1-methylethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 38, the title compound was synthesized in the samemanner as in Example 22. Yield: 82%. Melting point: 141-142° C. (ethylacetate-hexane). [α]_(D) ²⁰+40.8° (c=0.46, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.68 (3H, s),1.70 (3H, s), 1.86 (3H, s), 2.25 (2H, s), 2.35 (3H, s), 2.86 (1H,septet, J=6.9 Hz), 4.37 (1H, s), 4.37-4.50 (2H, m), 4.75-4.87 (1H, m),6.52 (1H, br s), 7.03 (2H, d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz).

EXAMPLE 47(+)-N-(tert-Butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

To a solution of(+)-(3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine(1.0 g, 3.55 mmol) obtained in Reference Example 141 in THF (10 mL) wasadded dropwise with ice-cooling 2,2,2-trichloroethyl chloroformate (0.49mL, 3.55 mmol), was added triethylamine (0.52 mL, 3.73 mmol) and thereaction mixture was stirred for 30 minutes, and then the reactionsolution was warmed to room temperature. Water was added to the reactionsolution, and the product was extracted with ethyl acetate. The organiclayer was washed with water, an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried over sodium sulfate,filtered, and then concentrated under reduced pressure. The solution ofthe obtained 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate(1.60 g, 3.50 mmol) and tert-butylamine (779 mg, 10.65 mmol) indimethylsulfoxide (20 mL) was stirred at 45° C. for 5 hours under anargon atmosphere. Water was added to the reaction solution, and theproduct was extracted with ethyl acetate. The organic layer was washedwith water, an aqueous saturated sodium hydrogen carbonate solution andsaturated brine, dried over sodium sulfate, filtered, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain1.19 g (yield: 88%) of the title compound. Melting point: 205-206° C.(ethyl acetate-hexane). [α]_(D) ²⁰=+81.0° (c=0.51, chloroform).

¹H-NMR (CDCl₃) δ: 1.18-1.30 (15H, m), 1.89 (3H, s), 2.25 (3H, s), 2.86(1H, septet, J=6.9 Hz), 4.00 (1H, br s), 4.45 (1H, dd, J=8.7, 4.8 Hz),4.53 (1H, dd, J=8.7, 4.8 Hz), 4.88 (1H, t, J=8.7 Hz), 5.25 (1H, br s),6.66 (1H, s), 7.00 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).

EXAMPLE 48(−)-N-(tert-Butyl)-N′-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using(+)-N-(tert-butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea,the title compound was synthesized in the same manner as in Example 20.Yield: 78%. Melting point: 209-210° C. (ethyl acetate-hexane). [α]_(D)²⁰=−31.2° (c=0.48, chloroform).

¹H-NMR (CDCl₃) δ: 1.10-1.40 (15H, m), 1.96 (3H, s), 2.57 (3H, s), 2.86(1H, septet, J=6.9 Hz), 3.97 (1H, br s), 4.50-4.63 (2H, m), 4.95-5.05(1H, m), 5.40 (1H, br s), 7.01 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1Hz), 10.47 (1H, s).

EXAMPLE 49(+)-N-(tert-Butyl)-N′-((3R)-7-(hydroxymethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using(−)-N-(tert-butyl)-N′-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)ureaobtained in Example 48, the title compound was synthesized in the samemanner as in Example 21. Yield: 97%. Melting point: 187-188° C. (ethylacetate-hexane). [α]_(D) ²⁰+34.0° (c=0.43, chloroform).

¹H-NMR (CDCl₃) δ: 1.12-1.28 (15H, m), 1.89 (3H, s), 2.05 (1H, br s),2.31 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.99 (1H, br s), 4.48 (1H,dd, J=9.0, 4.5 Hz), 4.56 (1H, dd, J=9.0, 4.5 Hz), 4.72-4.82 (2H, m),4.88 (1H, t, J=9.0 Hz), 5.30 (1H, br s), 6.97 (2H, d, J=8.1 Hz), 7.13(2H, d, J=8.1 Hz).

EXAMPLE 50(+)-N-(tert-Butyl)-N′-((3R)-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using(+)-N-(tert-butyl)-N′-((3R)-7-(hydroxymethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)ureaobtained in Example 49, the title compound was synthesized in the samemanner as in Example 45. Yield: 57%. Melting point: 209-210° C. (ethylacetate-hexane). [α]_(D) ²⁰=+53.2° (c=0.47, chloroform).

¹H-NMR (CDCl₃) δ: 1.10-1.38 (15H, m), 1.87 (3H, s), 2.19 (6H, s), 2.86(1H, septet, J=6.9 Hz), 3.99 (1H, br s), 4.44 (1H, dd, J=9.0, 4.5 Hz),4.54 (1H, dd, J=9.0, 4.5 Hz), 4.86 (1H, t, J=9.0 Hz), 5.29 (1H, br s),6.99 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 51(−)-N-((3R)-7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 37, the title compound was synthesized in the samemanner as in Example 35. Yield: 90%. Melting point: 118-119° C. (ethylacetate-hexane). [α]_(D) ²⁰=−13.0° (c=0.52, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.82 (3H, s),2.24 (2H, s), 2.32 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.51 (1H, dd,J=9.0, 4.5 Hz), 4.62 (1H, dd, J=9.0, 4.5 Hz), 4.93 (1H, t, J=9.0 Hz),6.56 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 52(+)-N-((3R)-3-(4-Isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 51, the title compound was synthesized in the samemanner as in Example 36. Yield: 98%. Melting point: 150-151° C. (ethylacetate-hexane). [α]_(D) ²⁰=+55.9° (c=0.50, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.82 (3H, s),2.15 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.88 (3H, s),4.44-4.53 (2H, m), 4.86 (1H, t, J=8.1 Hz), 6.48 (1H, br s), 7.03 (2H, d,J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 53N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)methanesulfonamide

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(200 mg, 0.68 mmol) obtained in Reference Example 30 and triethylamine(0.09 mL, 0.68 mmol) in THF (4 mL) was added dropwise methanesulfonylchloride (0.06 mL, 0.81 mmol) at 0° C. After the reaction solution wasstirred at room temperature for 30 minutes, the reaction solution wasadded to water and the product was extracted with ethyl acetate. Thecombined organic layers were washed with saturated brine, dried oversodium sulfate, and concentrated under reduced pressure. The obtainedresidue was purified by basic silica gel column chromatography (ethylacetate:hexane=3:2) to obtain 185 mg (yield: 73%) of the title compound.Melting point: 139-140° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.02 (3H, s), 2.18 (3H, s),2.33 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 2.99 (3H, s), 4.44 (1H, dd,J=4.5, 9.0 Hz), 4.53 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz),5.66 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 54N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butane-1-sulfonamide

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(200 mg, 0.68 mmol) obtained in Reference Example 30 in pyridine (10 mL)was added dropwise 1-butanesulfonyl chloride (0.11 mL, 0.82 mmol) at 0°C., was added 4-dimethylaminopyridine (91 mg, 0.75 mmol) and thereaction mixture was stirred for 6 hours. Water was added to thereaction solution and the product was extracted with ethyl acetate. Thecombined organic layers were washed with 1 N hydrochloric acid and anaqueous saturated sodium hydrogen carbonate solution, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by basic silica gel column chromatography(ethyl acetate:hexane=3:7) to obtain 174 mg (yield: 64%) of the titlecompound. Melting point: 96-97° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz), 1.44(2H, sixtet, J=7.5 Hz), 1.81-1.82 (2H, m), 2.01 (3H, s), 2.18 (3H, s),2.32 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.03-3.09 (2H, m), 4.43 (1H,dd, J=4.5, 9.0 Hz), 4.52 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0Hz), 5.58 (1H, s), 7.02 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 554,4,4-Trifluoro-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butane-1-sulfonamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and 4,4,4-trifluoro-1-butanesulfonylchloride, the title compound was synthesized in the same manner as inExample 53. Yield: 62%. Melting point: 149-150° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 2.00 (3H, s), 2.10-2.40 (10H,m), 2.86 (1H, septet, J=6.9 Hz), 3.14 (2H, t, J=7.3 Hz), 4.40-4.56 (2H,m), 4.84 (1H, t, J=8.9 Hz), 5.67 (1H, br s), 7.02 (2H, d, J=8.0 Hz),7.14 (2H, d, J=8.0 Hz).

EXAMPLE 56N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)ethanesulfonamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and ethanesulfonyl chloride, the titlecompound was synthesized in the same manner as in Example 54. Yield:56%. Melting point: 132-133° C. (ethanol).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.42 (3H, t, J=7.5 Hz), 2.02(3H, s), 2.18 (3H, s), 2.32 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 3.11(2H, q, J=7.5 Hz), 4.43 (1H, dd, J=8.7, 4.8 Hz), 4.52 (1H, dd, J=9.6,5.1 Hz), 4.83 (1H, t, J=9.0 Hz), 5.53 (1H, br s), 7.02 (2H, d, J=8.1Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 57N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)propane-1-sulfonamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and 1-propanesulfonyl chloride, thetitle compound was synthesized in the same manner as in Example 54.Yield: 54%. Melting point: 133-134° C. (ethanol).

¹H-NMR (CDCl₃) δ: 1.04 (3H, t, J=7.2 Hz), 1.22 (6H, d, J=6.9 Hz),1.81-2.05 (5H, m), 2.18 (3H, s), 2.32 (3H, s), 2.86 (1H, septet, J=6.9Hz), 3.00-3.09 (2H, m), 4.40-4.58 (2H, m), 4.84 (1H, t, J=8.7 Hz), 5.55(1H, br s), 7.02 (2H, d, J=7.5 Hz), 7.13 (2H, d, J=7.5 Hz).

EXAMPLE 58(3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide

Using3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 32, the title compound was synthesized inthe same manner as in Reference Example 73. Yield: 81%. Melting point:193-196° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.19-1.25 (6H, m), 1.87 (1.5H, s), 1.91 (1.5H, s),2.22 (1.5H, s), 2.26 (1.5H, s), 2.79-2.93 (1H, m), 4.39-4.58 (2H, m),4.79-4.90 (1H, m), 6.59-6.80 (2H, m), 6.98-7.04 (2H, m), 7.10-7.16 (2H,m), 7.94 (0.5H, d, J=12.6 Hz), 8.35 (0.5H, d, J=1.2 Hz).

¹H-NMR (CDCl₃)

EXAMPLE 59(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide

Using(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 58, the title compound was synthesized in the samemanner as in Example 35. Yield: 91%. Melting point: 151-152° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.18-1.30 (6H, m), 1.82-1.92 (3H, m), 2.32-2.44 (3H,m), 2.80-2.97 (1H, m), 4.45-4.65 (2H, m), 4.89-5.00 (1H, m), 6.80 (1H,br s), 7.00-7.17 (4H, m), 7.91 (0.4H, d, J=12.0 Hz), 8.35 (0.6H, d,J=1.5 Hz).

EXAMPLE 60(7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide

Using(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 58, the title compound was synthesized in the samemanner as in Example 20. Yield: 92%. Melting point: 123-124° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.20-1.25 (6H, m), 1.94 (1.8H, s), 1.97 (1.2H, s),2.53 (1.8H, s), 2.58 (1.2H, s), 2.80-2.95 (1H, m), 4.47-4.63 (2H, m),4.93-5.04 (1H, m), 6.67 (1H, br s), 7.00-7.06 (2H, m), 7.12-7.18 (2H,m), 7.91 (0.4H, d, J=12.0 Hz), 8.39 (0.6H, d, J=1.2 Hz), 10.4 (0.6H, s),10.5 (0.4H, s).

EXAMPLE 61 Ethyl3-(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate

Using ethyl3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoateobtained in Reference Example 321, the title compound was synthesized inthe same manner as in Example 1. Yield: 59%. Melting point: 150-151° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.26 (3H, t,J=6.9 Hz), 1.84 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 2.54 (2H, dd,J=9.0, 6.0 Hz), 2.85 (1H, septet, J=6.9 Hz), 2.96 (2H, dd, J=10.2, 7.2Hz), 4.14 (2H, q, J=6.9 Hz), 4.40 (1H, dd, J=8.7, 4.8 Hz), 4.50 (1H, dd,J=9.3, 4.5 Hz), 4.81 (1H, t, J=9.3 Hz), 6.47 (1H, br s), 7.02 (2H, d,J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 62N-(7-(3-Hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propan-1-olobtained in Reference Example 322, the title compound was synthesized inthe same manner as in Example 1. Yield: 36%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.66-1.90 (5H,m), 2.18 (3H, s), 2.24 (2H, s), 2.56 (1H, br s), 2.77 (2H, t, J=6.9 Hz),2.86 (1H, septet, J=6.9 Hz), 3.50-3.65 (2H, m), 4.43 (1H, dd, J=8.7, 4.5Hz), 4.53 (1H, dd, J=8.7, 4.5 Hz), 4.81 (1H, t, J=8.7 Hz), 6.59 (1H, brs), 7.02 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 63N-(4-Bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(4-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)amineobtained in Reference Example 323, the title compound was synthesized inthe same manner as in Example 1. Yield: 51%. Melting point: 150-151° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.22 (6H, d, J=6.9 Hz), 2.17 (3H, s),2.18 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.44-4.57 (2H,m), 4.83 (1H, t, J=7.5 Hz), 6.64 (1H, br s), 7.06 (2H, d, J=8.4 Hz),7.12 (2H, d, J=8.4 Hz).

EXAMPLE 64N-(3-(4-Isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 315, the title compound was synthesized inthe same manner as in Example 1. Yield: 61%. Melting point: 135-136° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.84 (3H, s),2.19 (2H, s), 2.22 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd,J=8.7, 4.8 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz), 4.83 (1H, t, J=9.0 Hz),6.64 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.15(1H, s)

EXAMPLE 65N-(3-(4-Isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amineobtained in Reference Example 316, the title compound was synthesized inthe same manner as in Example 1. Yield: 58%. Melting point: 214-215° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.16 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.04 (3H, s), 2.14 (3H, s), 2.31 (2H, s), 2.87 (1H, septet, J=6.9 Hz),4.40 (1H, dd, J=8.7, 4.5 Hz), 4.52 (1H, dd, J=9.0, 4.5 Hz), 4.81 (1H, t,J=9.0 Hz), 6.60 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1Hz).

EXAMPLE 66N-(3-(4-Isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amineobtained in Reference Example 317, the title compound was synthesized inthe same manner as in Example 1. Yield: 59%. Melting point: 190-191° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.09 (3H, s), 2.16 (3H, s), 2.29 (2H, s), 2.86 (1H, septet, J=6.9 Hz),4.38 (1H, dd, J=8.7, 5.1 Hz), 4.55 (1H, dd, J=9.3, 4.5 Hz), 4.81 (1H, t,J=9.3 Hz), 6.71 (1H, br s), 7.04 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4Hz).

EXAMPLE 674-(Benzyloxy)-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and 4-benzyloxybutyryl chloride, thetitle compound was synthesized in the same manner as in Example 1.Yield: 52%. Melting point: 85-86° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.78 (3H, s), 1.98-2.21 (8H,m), 2.50 (2H, t, J=6.9 Hz), 2.86 (1H, septet, J=6.9 Hz), 3.58 (2H, t,J=6.0 Hz), 4.37-4.56 (4H, m), 4.81 (1H, t, J=9.0 Hz), 6.80 (1H, br s),7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz), 7.18-7.37 (5H, m).

EXAMPLE 68N-(3-(4-Isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-amineobtained in Reference Example 318, the title compound was synthesized inthe same manner as in Example 1. Yield: 29%. Melting point: 183-184° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.18 (9H, s), 1.22 (6H, d, J=6.9 Hz), 2.03 (3H, s),2.37 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.64 (1H, dd, J=8.7, 5.1 Hz),4.72 (1H, dd, J=8.4, 4.5 Hz), 5.05 (1H, t, J=9.0 Hz), 6.86 (1H, br s),7.06 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.37-7.52 (2H, m), 7.80(1H, d, J=8.1 Hz), 8.00 (1H, d, J=8.1 Hz).

EXAMPLE 69N-(3-(4-Isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4-methyl-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-5-amineobtained in Reference Example 319, the title compound was synthesized inthe same manner as in Example 1. Yield: 62%. Melting point: 183-184° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.68-1.95 (7H,m), 2.24 (2H, s), 2.55-2.70 (4H, m), 2.86 (1H, septet, J=6.9 Hz), 4.43(1H, dd, J=8.7, 5.1 Hz), 4.52 (1H, dd, J=9.0, 5.1 Hz), 4.84 (1H, t,J=9.0 Hz), 6.38 (1H, br s), 7.06 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1Hz).

EXAMPLE 70N-(3-(4-Isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-5-amineobtained in Reference Example 320, the title compound was synthesized inthe same manner as in Example 1. Yield: 59%. Melting point: 201-202° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.04-2.28 (4H, m), 2.77-3.01 (5H, m), 4.41-4.57 (2H, m), 4.85 (1H, t,J=8.1 Hz), 6.52 (1H, br s), 7.05 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1Hz).

EXAMPLE 71N-((3S)-3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 326, the title compound was synthesized inthe same manner as in Example 1. Yield: 84%. Melting point: 147-148° C.(hexane-ethyl acetate). [α]_(D) ²⁰=−93° (c=0.497, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.21 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 4.40 (1H, dd,J=8.4, 4.8 Hz), 4.49 (1H, dd, J=9.0, 4.8 Hz), 4.82 (1H, t, J=9.0 Hz),6.49 (1H, br s), 6.62 (1H, s), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d,J=8.1 Hz).

EXAMPLE 72N-(3-(3-Methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 302, the title compound was synthesized inthe same manner as in Example 1. Yield: 87%. Melting point: 169-170° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.85 (3H, s), 2.14 (3H, s), 2.17 (3H,s), 2.25 (2H, s), 3.76 (3H, s), 4.41 (1H, dd, J=4.8, 9.0 Hz), 4.53 (1H,dd, J=4.8, 9.0 Hz), 4.83 (1H, t, J=8.7 Hz), 6.50 (1H, br s), 6.68-6.76(3H, m), 7.19 (1H, t, J=7.8 Hz).

EXAMPLE 73N-(3-(3-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 301, the title compound was synthesized inthe same manner as in Example 1. Yield: 91%. Melting point: 168-169° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.82 (3H, s), 2.14 (3H, s), 2.17 (3H,s), 2.25 (2H, s), 3.98-4.17 (4H, m), 4.32 (1H, dd, J=5.0, 8.8 Hz), 4.58(1H, dd, J=5.0, 8.8 Hz), 4.84 (1H, t, J=8.8 Hz), 5.75 (1H, s), 6.49 (1H,br s), 7.08-7.12 (1H, m), 7.24-7.37 (3H, m).

EXAMPLE 74N-(4-Isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 303, the title compound was synthesized inthe same manner as in Example 1. Yield: 97%. Melting point: 195-196° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.18 (6H, d, J=6.9 Hz), 1.88 (3H, s),2.16 (6H, s), 2.27 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 3.86 (3H, s),4.33 (1H, dd, J=3.3, 8.4 Hz), 4.82 (1H, t, J=8.4 Hz), 4.87 (1H, dd,J=3.3, 8.4 Hz), 6.54 (1H, br s), 6.66 (2H, s), 6.72 (1H, s).

EXAMPLE 753,3-Dimethyl-N-(4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using 4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtainedin Reference Example 306, the title compound was synthesized in the samemanner as in Example 1. Yield: 50%. Melting point: 146-147° C. (ethylacetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.83 (3H, s), 2.15 (3H, s), 2.20 (3H,s), 2.25 (2H, s), 4.41 (1H, dd, J=4.8, 9.0 Hz), 4.56 (1H, dd, J=4.8, 9.0Hz), 4.84 (1H, t, J=9.0 Hz), 6.50 (1H, br s), 7.06-7.18 (2H, m),7.20-7.30 (3H, m).

EXAMPLE 763,3-Dimethyl-N-(4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 307, the title compound was synthesized inthe same manner as in Example 1. Yield: 80%. Melting point: 176-177° C.(ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.82 (3H, s), 2.13 (3H, s), 2.17 (3H,s), 2.23 (2H, s), 2.30 (3H, s), 4.38 (1H, dd, J=4.8, 9.0 Hz), 4.51 (1H,dd, J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 6.57 (1H, br s), 6.98 (2H,d, J=8.1 Hz), 7.07 (2H, d, J=8.1 Hz).

EXAMPLE 77N-(3-(Biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 309, the title compound was synthesized inthe same manner as in Example 1. Yield: 71%. Melting point: 218-219° C.(ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.88 (3H, s), 2.16 (3H, s), 2.19 (3H,s), 2.26 (2H, s), 4.45 (1H, dd, J=4.5, 9.0 Hz), 4.60 (1H, dd, J=4.5, 9.0Hz), 4.87 (1H, t, J=9.0 Hz), 6.52 (1H, br s), 7.20 (2H, d, J=8.4 Hz),7.32 (1H, t, J=8.4 Hz), 7.42 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz),7.55 (2H, d, J=8.4 Hz).

EXAMPLE 783,3-Dimethyl-N-(4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using4,6,7-trimethyl-3-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 308, the title compound was synthesized inthe same manner as in Example 1. Yield: 78%. Melting point: 170-171° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.87 (3H, s), 2.05 (3H, s), 2.14 (3H,s), 2.17 (3H, s), 2.26 (2H, s), 4.55 (1H, dd, J=4.5, 9.0 Hz), 4.74 (1H,dd, J=4.5, 9.0 Hz), 4.88 (1H, t, J=9.0 Hz), 6.54 (1H, br s), 6.91 (1H,d, J=8.4 Hz), 7.38 (1H, dd, J=1.8, 8.4 Hz), 8.36 (1H, d, J=1.8 Hz).

EXAMPLE 793,3-Dimethyl-N-(3-(4-ethylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using 3-(4-ethylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 314, the title compound was synthesized inthe same manner as in Example 1. Yield: 87%. Melting point: 162-163° C.(THF-diisopropyl ether).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.20 (3H, t, J=7.5 Hz), 1.84 (3H, s),2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.60 (2H, q, J=7.5 Hz), 4.40(1H, dd, J=4.8, 9.0 Hz), 4.53 (1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t,J=9.0 Hz), 6.50 (1H, br s), 7.04 (2H, d, J=8.4 Hz), 7.10 (2H, d, J=8.4Hz)

EXAMPLE 80N-(3-(4-Isobutylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 3-(4-isobutylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amine obtainedin Reference Example 312,3-(4-isobutylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-aminewas synthesized in the same manner as in Reference Example 144. Usingthis compound and tert-butylacetyl chloride, the title compound wassynthesized in the same manner as in Example 1. Yield: 34%. Meltingpoint: 153-154° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.87 (6H, d, J=6.9 Hz), 1.12 (9H, s), 1.72-1.86 (4H,m), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.42 (2H, d, J=7.2 Hz),4.40 (1H, dd, J=4.5, 9.0 Hz), 4.53 (1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t,J=9.0 Hz), 6.51 (1H, br s), 7.03 (4H, s).

EXAMPLE 81N-(3-(4-Cyclohexylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 3-(4-cyclohexylphenyl)-4,6,7-trimethyl-1-benzofuran-5-amineobtained in Reference Example 313,3-(4-cyclohexylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-aminewas synthesized in the same manner as in Reference Example 144. Usingthis compound, the title compound was synthesized in the same manner asin Example 1. Yield: 43%. Melting point: 146-148° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.19-1.45 (4H, m), 1.70-1.95 (9H, m),2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.45 (1H, br), 4.41 (1H, dd,J=4.8, 9.0 Hz), 4.52 (1H, dd, J=4.8, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz),6.51 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 82N-(3-(4-(1,3-Dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 310, the title compound was synthesized inthe same manner as in Example 1. Yield: 96%. Melting point: 193-194° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.81 (3H, s), 2.14 (3H, s), 2.17 (3H,s), 2.25 (2H, s), 3.99-4.06 (2H, m), 4.07-4.14 (2H, m), 4.36 (1H, dd,J=4.5, 9.0 Hz), 4.57 (1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz),5.76 (1H, s), 6.47 (1H, br s), 7.14 (2H, d, J=8.1 Hz), 7.38 (2H, d,J=8.1 Hz).

EXAMPLE 83N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution ofN-(7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(1.23 g, 3.02 mmol) obtained in Example 22 and p-toluenesulfonic acidmonohydrate (20 mg) in toluene (20 mL) was refluxed with heating at 80°C. for 1 hour under an argon atmosphere. The reaction solution waswashed with an aqueous saturated sodium hydrogen carbonate solution,dried over magnesium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:9) to obtain 1.09 g (yield: 89%) of the titlecompound. Melting point: 171-172° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.246 (3H, s), 2.249 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 4.42-4.58(2H, m), 4.80-4.92 (1H, m), 5.49 (1H, dd, J=11.7, 2.1 Hz), 5.92 (1H, dd,J=17.7, 2.1 Hz), 6.51 (1H, br s), 6.76 (1H, dd, J=17.7, 11.7 Hz), 7.04(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 84N-(7-(1,2-Dihydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of AD-mix β (4.62 g) in a mixed solvent of water (15 mL),tert-butanol (15 mL) and THF (15 mL) was added with ice-coolingN-(3-(4-isopropylphenyl)-4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(670 mg, 1.65 mmol) obtained in Example 83 and the reaction mixture wasstirred at 80° C. for 3 hours. To the reaction solution were added waterand sodium sulfite and the resulting mixture was stirred at roomtemperature for 30 minutes. The product was extracted with ethylacetate, and the organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and the solvent wasdistilled off under reduced pressure.

The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:20) to obtain 558 mg (yield: 77%) of the titlecompound. Melting point: 159-161° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.10-2.24 (5H, m), 2.86 (1H, septet, J=6.9 Hz), 3.60-3.84 (2H, m),4.40-4.57 (2H, m), 4.80-5.00 (2H, m), 6.70 (1H, br s), 7.01 (2H, d,J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 2H unidentified.

EXAMPLE 85N-(7-(2-Hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution ofN-(7-(1,2-dihydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(200 mg, 0.455 mmol) obtained in Example 84 and palladium hydroxide oncarbon (20 mg) in ethanol (20 mL) was stirred at 60° C. for 3 hoursunder a hydrogen atmosphere. The catalyst was removed and the reactionsolution was concentrated under reduced pressure. Water was added to theresidue and the product was extracted with ethyl acetate. The organiclayer was washed with water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=7:3) to obtain40 mg (yield: 21%) of the title compound. Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.20 (3H, s), 2.25 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 2.94 (2H, t,J=6.6 Hz), 3.80 (2H, t, J=6.6 Hz), 4.40 (1H, dd, J=8.4, 4.8 Hz), 4.52(1H, dd, J=9.0, 5.1 Hz), 4.81 (1H, t, J=9.0 Hz), 6.53 (1H, br s), 7.02(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz), 1H unidentified.

EXAMPLE 86N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-propionyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using a diastereo mixture ofN-(7-(1-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in the synthesis in Examples 30 and 31, the title compound wassynthesized in the same manner as in Example 32. Yield: 18%. Meltingpoint: 163-164° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.16 (3H, t, J=7.4 Hz), 1.22 (6H, d,J=7.0 Hz), 1.88 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.78-3.01 (3H, m),4.43-4.57 (2H, m), 4.87 (1H, t, J=8.0 Hz), 6.48 (1H, br s), 7.03 (2H, d,J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz).

EXAMPLE 87N-(6-Bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 64, the title compound was synthesized in the samemanner as in Reference Example 23. Yield: 32%. Melting point: 174-175°C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s),2.26 (2H, s), 2.31 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.44 (1H, dd,J=8.7, 4.5 Hz), 4.52 (1H, dd, J=9.0, 4.8 Hz), 4.93 (1H, t, J=9.0 Hz),6.68 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 88N-(3-(4-Isopropylphenyl)-4-methoxy-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(4-bromo-3-(4-isopropylphenyl)-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 63, the title compound was synthesized in the samemanner as in Example 36. Yield: 21%. Melting point: 161-162° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 2.13 (3H, s),2.15 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.44 (3H, s),4.41 (1H, dd, J=8.4, 4.8 Hz), 4.71 (1H, dd, J=9.3, 4.8 Hz), 4.82 (1H,dd, J=9.3, 8.4 Hz), 6.66 (1H, br s), 7.08 (2H, d, J=8.1 Hz), 7.14 (2H,d, J=8.1 Hz).

EXAMPLE 89N-(3-(4-Isopropylphenyl)-6-methoxy-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 87, the title compound was synthesized in the samemanner as in Example 36. Yield: 37%. Melting point: 162-163° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.83 (3H, s),2.17 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.69 (3H, s),4.42 (1H, dd, J=8.7, 4.8 Hz), 4.51 (1H, dd, J=9.0, 5.1 Hz), 4.83 (1H, t,J=8.7 Hz), 6.67 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1Hz).

EXAMPLE 90N-(7-(1-Hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To propylmagnesium chloride (2.0 M, THF solution 10.0 mL, 20.0 mmol) wasaddedN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(2.2 g, 5.40 mmol) obtained in Example 20 at 0° C. and the reactionsolution was stirred at the same temperature for 1 hour. The reactionsolution was added to water and the product was extracted with ethylacetate. The organic layer was washed with water and 1 N hydrochloricacid, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=4:1) to obtain 627 mg (yield: 26%)of the title compound as a low polarity isomer. Melting point: 162-163°C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 0.87-1.05 (3H, m), 1.11 (9H, s), 1.22 (6H, d, J=7.0Hz), 1.30-2.00 (7H, m), 2.15 (3H, s), 2.24 (2H, s), 2.86 (1H, septet,J=7.0 Hz), 3.30 (1H, d, J=10.2 Hz), 4.40-4.58 (2H, m), 4.78-4.92 (2H,m), 6.54 (1H, br s), 7.02 (2H, d, J=8.2 Hz), 7.12 (2H, d, J=8.2 Hz).

EXAMPLE 91N-(7-(1-Hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

The residue treated in the same manner as described in the Example 90was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to obtain 547 mg (yield: 22%) of the title compound as ahigh polarity isomer. Melting point: 150-151° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 0.88-1.04 (3H, m), 1.12 (9H, s), 1.22 (6H, d, J=7.0Hz), 1.30-2.00 (7H, m), 2.19 (3H, s), 2.25 (2H, s), 2.86 (1H, septet,J=7.0 Hz), 3.28 (1H, d, J=10.2 Hz), 4.40-4.55 (2H, m), 4.79-4.93 (2H,m), 6.47 (1H, br s), 7.02 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz).

EXAMPLE 92N-(7-Butyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using a diastereo mixture ofN-(7-(1-hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Examples 90 and 91, the title compound was synthesized inthe same manner as in Example 23. Yield: 33%. Melting point: 149-151° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 0.83-1.00 (3H, m), 1.11 (9H, s), 1.21 (6H, d, J=6.9Hz), 1.34-1.58 (4H, m), 1.83 (3H, s), 2.16 (3H, s), 2.23 (2H, s), 2.62(2H, t, J=7.5 Hz), 2.85 (1H, septet, J=6.9 Hz), 4.39 (1H, dd, J=8.4, 4.5Hz), 4.49 (1H, dd, J=9.0, 4.5 Hz), 4.79 (1H, t, J=9.0 Hz), 6.52 (1H, brs), 7.03 (2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 934-Hydroxy-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(300 mg, 1.02 mmol) obtained in Reference Example 30 in THF (20 mL) wasadded dropwise at 0° C. under an argon atmosphere n-butyllithium (1.6 M,hexane solution, 1.25 mL, 2.04 mmol) and the resulting mixture wasstirred at the same temperature for 1 hour. To the reaction solution wasadded dropwise γ-butyrolactone (300 mg, 0.98 mmol) and the resultingmixture was stirred for 1 hour. Water was added to the reaction solutionand the product was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (ethylacetate:hexane=1:1) to obtain 174 mg (yield: 45%) of the title compound.Melting point: 156-157° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.20-1.30 (6H, m), 1.80-2.20 (11H, m), 2.56 (2H, t,J=6.8 Hz), 2.70 (1H, br s), 2.86 (1H, septet, J=6.9 Hz), 3.55-3.78 (2H,m), 4.38-4.57 (2H, m), 4.78-4.90 (1H, m), 6.78 (1H, br s), 7.00-7.18(4H, m).

EXAMPLE 94N-(7-(Hydroxy(phenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution of bromobenzene (770 mg, 4.91 mmol) in THF (10 mL) was addedunder an argon atmosphere to a mixture of magnesium (119 mg, 4.91 mmol)and a catalytic amount of iodine, and the resulting mixture was stirredat room temperature for 20 minutes. To the reaction solution was addeddropwise a solution ofN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(400 mg, 0.98 mmol) obtained in Example 20 in THF (5 mL) and theresulting mixture was stirred at room temperature for 1 hour. Thereaction solution was added to ice and the product was extracted withethyl acetate. The organic layer was washed with 1 N hydrochloric acidand water, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:2) to obtain 512 mg (yield: 99%)of the title compound. Yield: 99%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s),2.15 (3H, s), 2.24 (2H, s), 2.78-2.91 (1H, m), 3.88-3.99 (1H, m),4.37-4.55 (2H, m), 4.75-4.90 (1H, m), 6.03 (1H, d, J=9.3 Hz), 6.58-6.62(1H, m), 6.98-7.45 (9H, m)

EXAMPLE 95N-(7-(Hydroxy(4-isopropylphenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 4-isopropyl-1-bromobenzene, the title compound was synthesized inthe same manner as in Example 94.

Yield: 70%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.18-1.31 (12H, m), 1.89 (3H, s), 2.13(3H, s), 2.23 (2H, s), 2.79-2.95 (2H, m), 3.89-4.07 (1H, m), 4.39-4.48(2H, m), 4.77-4.91 (1H, m), 5.98 (1H, d, J=8.4 Hz), 6.55 (1H, d, J=6.6Hz), 6.98-7.22 (6H, m), 7.29 (2H, d, J=8.1 Hz).

EXAMPLE 96N-(7-Benzyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution ofN-(7-(hydroxy(phenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(512 mg, 1.05 mmol) obtained in Example 94 and 10% palladium on carbon(water content: 50%, 50 mg) in acetic acid (20 mL) was stirred at 80° C.for 1.5 hours under hydrogen atmosphere. The catalyst was removed andthe reaction solution was concentrated under reduced pressure. Water wasadded to the residue and the product was extracted with ethyl acetate.The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue wasrecrystallized from hexane-ethyl acetate to obtain 330 mg (yield: 67%)of the title compound. Melting point: 153-154° C.

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s),2.10 (3H, s), 2.23 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.04 (2H, s),4.43 (1H, dd, J=8.4, 4.2 Hz), 4.56 (1H, dd, J=9.0, 4.8 Hz), 4.83 (1H, t,J=9.0 Hz), 6.46 (1H, br s), 7.03-7.28 (9H, m).

EXAMPLE 97N-(7-(4-Isopropylbenzyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-(hydroxy(4-isopropylphenyl)methyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 95, the title compound was synthesized in the samemanner as in Example 96. Yield: 64%. Melting point: 157-158° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.22 (6H, d,J=6.9 Hz), 1.87 (3H, s), 2.10 (3H, s), 2.22 (2H, s), 2.77-2.92 (2H, m),3.99 (2H, s), 4.42 (1H, dd, J=9.0, 4.8 Hz), 4.55 (1H, dd, J=9.3, 4.8Hz), 4.82 (1H, t, J=9.0 Hz), 6.45 (1H, br s), 7.00-7.17 (8H, m).

EXAMPLE 985-((3,3-Dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylicacid

To a mixed solution ofN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(500 mg, 1.23 mmol) obtained in Example 20, sodium dihydrogenphosphate(40 mg), and hydrogen peroxide (0.125 mL) in acetonitrile (5 mL)-water(2 mL) was added at room temperature a solution of sodium chlorite (190mg, 1.69 mmol) in water (2 mL) and the resulting mixture was stirred atthe same temperature for 2 hours. To the reaction solution was added anaqueous sodium hydrogensulfite solution, added 1 N hydrochloric acid tomake the mixture acidic, and the mixture was extracted with ethylacetate. The extracts were washed with water, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The obtainedresidue was crystallized from hexane-ethyl acetate to obtain 380 mg(yield: 73%) of the title compound. Melting point: 194-195° C.

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, m),2.28 (2H, s), 2.51 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.47-4.65 (2H,m), 5.01 (1H, t, J=9.0 Hz), 6.59 (1H, br s), 7.02 (2H, d, J=8.1 Hz),7.14 (2H, d, J=8.1 Hz), 1H unidentified.

EXAMPLE 99N-(7-Cyano-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution ofN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(0.5 g, 1.09 mmol) obtained in Example 35 and copper cyanide (300 mg3.27 mmol) in dimethylsulfoxide (30 mL) was heated at 180° C. for 14hours. To the reaction solution was added aqueous ammonia and theproduct was extracted with ethyl acetate. The extracts were washed withsaturated brine, dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate 3:1)to obtain 360 mg (yield: 82%) of the title compound. Melting point:135-136° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s),2.25 (2H, s), 2.38 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.50-4.65 (2H,m), 5.01 (1H, t, J=10.8 Hz), 6.58 (1H, br s), 7.02 (2H, d, J=8.1 Hz),7.15 (2H, d, J=8.1 Hz).

EXAMPLE 100N-((3S)-7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-((3S)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 71, the title compound was synthesized in the samemanner as in Example 38. Yield: 46%. Melting point: 177-178° C.(hexane-ethyl acetate). [α]_(D) ²⁰=−6.0° (c=0.510, chloroform).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s),2.22 (3H, s), 2.25 (2H, s), 2.58 (3H, s), 2.87 (1H, septet, J=6.9 Hz),4.44-4.56 (2H, m), 4.89 (1H, t, J=8.1 Hz), 6.54 (1H, br s), 7.03 (2H, d,J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz).

EXAMPLE 101N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixture ofN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(300 mg, 0.654 mmol) obtained in Example 35, phenylboronic acid (88 mg,0.720 mmol), and palladium (0) tetrakis(triphenylphosphine) (27 mg,0.023 mmol) in an aqueous 2 M sodium carbonate solution (10mL)-1,2-dimethoxyethane (5 mL) was refluxed with heating for 16 hoursunder a nitrogen atmosphere. The reaction solution was diluted withethyl acetate. Insoluble materials were filtered off, and the filtratewas washed with saturated brine and dried over anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:4) to obtain 170 mg (yield: 57%) of the title compound.Melting point: 178-182° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.06 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.37 (1H, dd,J=9.0, 4.8 Hz), 4.56 (1H, dd, J=9.3, 5.1 Hz), 4.79 (1H, t, J=9.0 Hz),6.59 (1H, br s), 7.09 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz),7.30-7.50 (5H, m).

EXAMPLE 102N-(3-(4-Isopropylphenyl)-7-(6-methoxypyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (6-methoxypyridin-3-yl)boronic acid, thetitle compound was synthesized in the same manner as in Example 101.Yield: 48%. Melting point: 120-123° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.08 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.97 (3H, s),4.38 (1H, dd, J=8.7, 4.8 Hz), 4.56 (1H, dd, J=9.3, 5.1 Hz), 4.79 (1H, t,J=9.3 Hz), 6.52 (1H, br s), 6.81 (1H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4Hz), 7.13 (2H, d, J=8.4 Hz), 7.57 (1H, dd, J=8.4, 2.4 Hz), 8.13 (1H, d,J=2.4 Hz).

EXAMPLE 103N-(3-(4-Isopropylphenyl)-7-(4-methoxyphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (4-methoxyphenyl)boronic acid, the titlecompound was synthesized in the same manner as in Example 101. Yield:40%. Melting point: 129-131° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.07 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 3.84 (3H, s),4.38 (1H, dd, J=9.0, 4.8 Hz), 4.56 (1H, dd, J=9.3, 4.8 Hz), 4.79 (1H, t,J=9.0 Hz), 6.53 (1H, br s), 6.97 (2H, d, J=8.7 Hz), 7.09 (2H, d, J=8.4Hz), 7.14 (2H, d, J=8.4 Hz), 7.27 (2H, d, J=8.7 Hz).

EXAMPLE 104N-(7-(6-Fluoropyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (6-fluoropyridin-3-yl)boronic acid, the titlecompound was synthesized in the same manner as in Example 101. Yield:58%. Melting point: 135-137° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.93 (3H, s),2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.38 (1H, dd,J=8.7, 4.8 Hz), 4.58 (1H, dd, J=9.0, 4.8 Hz), 4.81 (1H, t, J=9.0 Hz),6.60 (1H, br s), 7.00 (1H, dd, J=8.4, 3.0 Hz), 7.08 (2H, d, J=8.1 Hz),7.15 (2H, d, J=8.1 Hz), 7.79 (1H, dt, J=8.4, 2.1 Hz), 8.19 (1H, s).

EXAMPLE 105N-(3-(4-Isopropylphenyl)-7-(3-methoxyphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (3-methoxyphenyl)boronic acid, the titlecompound was synthesized in the same manner as in Example 101. Yield:64%. Melting point: 209-210° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 3.82 (3H, s),4.38 (1H, dd, J=8.7, 4.8 Hz), 4.56 (1H, dd, J=9.0, 5.1 Hz), 4.80 (1H, t,J=9.0 Hz), 6.52 (1H, br s), 6.86-6.94 (3H, m), 7.10 (2H, d, J=8.1 Hz),7.14 (2H, d, J=8.1 Hz), 7.35 (1H, dd, J=8.7, 7.8 Hz).

EXAMPLE 106N-(3-(4-Isopropylphenyl)-4,7-dimethyl-6-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 87 and phenylboronic acid, the title compound wassynthesized in the same manner as in Example 101. Yield: 42%. Meltingpoint: 212-213° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 0.82 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.85-1.93 (8H,m), 2.88 (1H, septet, J=6.9 Hz), 4.48 (1H, dd, J=8.7, 4.8 Hz), 4.60 (1H,dd, J=9.0, 5.1 Hz), 4.89 (1H, t, J=9.0 Hz), 6.21 (1H, br s), 7.09-7.43(9H, m).

EXAMPLE 107N-(7-(3-(Acetylamino)phenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution ofN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(321 mg, 0.7 mmol) obtained in Example 35,(3-(acetylamino)phenyl)boronic acid (188 mg, 0.7 mmol), palladium(0)tetrakis(triphenylphosphine) (40.5 mg, 0.035 mmol), and an aqueous 2 Nsodium carbonate solution (1.05 mL) in dimethoxyethane (2.1 mL)-ethanol(0.7 mL) was reacted with heating at 150° C. for 5 minutes in amicrowave reactor. The reaction solution was cooled to room temperature,diluted with water, and extracted with ethyl acetate. The filtrate waswashed with saturated brine and dried over sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain308 mg (yield: 86%) of the title compound. Melting point: 247-248° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.05 (3H, s), 2.15 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz),4.36 (1H, dd, J=4.9, 9.0 Hz), 4.54 (1H, dd, J=4.9, 9.0 Hz), 4.77 (1H, t,J=9.0 Hz), 6.54 (1H, s), 7.07-7.15 (5H, m), 7.26-7.39 (3H, m), 7.60 (1H,br).

EXAMPLE 108N-(7-(3-Fluorophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (3-fluorophenyl)boronic acid, the titlecompound was synthesized in the same manner as in Example 107. Yield:67%. Melting point: 182-183° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.06 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.38 (1H, dd,J=4.9, 9.0 Hz), 4.56 (1H, dd, J=4.9, 9.0 Hz), 4.80 (1H, t, J=9.0 Hz),6.51 (1H, s), 6.99-7.17 (7H, m), 7.34-7.42 (1H, m).

EXAMPLE 109N-(7-(3-Nitrophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (3-nitrophenyl)boronic acid, the titlecompound was obtained in the same manner as in Example 107. Yield: 59%.Melting point: 209-210° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.94 (3H, s),2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.38 (1H, dd,J=4.9, 9.0 Hz), 4.57 (1H, dd, J=4.9, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz),6.52 (1H, s), 6.63-6.73 (3H, m), 7.07 (2H, d, J=8.2 Hz), 7.15 (2H, d,J=8.2 Hz), 7.59 (1H, t, J=7.7 Hz), 7.66-7.71 (1H, m), 8.17-8.23 (2H, m).

EXAMPLE 110 Methyl3-(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)benzoate

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (3-methoxycarbonyl)phenylboronic acid, thetitle compound was obtained in the same manner as in Example 107. Yield:55%. Melting point: 206-208° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s),2.05 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 3.91 (3H, s),4.37 (1H, dd, J=4.9, 9.0 Hz), 4.57 (1H, dd, J=4.9, 9.0 Hz), 4.80 (1H, t,J=9.0 Hz), 6.57 (1H, s), 7.08 (2H, d, J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz),7.47-7.56 (2H, m), 7.98-8.03 (2H, m).

EXAMPLE 111N-(7-(3-Acetylphenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (3-acetylphenyl)boronic acid, the titlecompound was obtained in the same manner as in Example 107. Yield: 79%.Melting point: 209-210° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s),2.05 (3H, s), 2.27 (2H, s), 2.62 (3H, s), 2.87 (1H, septet, J=6.9 Hz),4.37 (1H, dd, J=4.9, 9.0 Hz), 4.57 (1H, dd, J=4.9, 9.0 Hz), 4.80 (1H, t,J=9.0 Hz), 6.53 (1H, s), 7.08 (2H, d, J=8.2 Hz), 7.14 (2H, d, J=8.2 Hz),7.50-7.56 (2H, m), 7.91-7.97 (2H, m).

EXAMPLE 112 Ethyl3-(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)benzoate

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and 3-(ethoxycarbonyl)phenylboronic acid, thetitle compound was obtained in the same manner as in Example 107. Yield:63%. Melting point: 175-177° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.39 (3H, t,J=7.1 Hz), 1.93 (3H, s), 2.04 (3H, s), 2.27 (2H, s), 2.87 (1H, septet,J=6.9 Hz), 4.34-4.42 (3H, m), 4.57 (1H, dd, J=4.7, 9.3 Hz), 4.79 (1H,dd, J=8.8, 9.3 Hz), 6.52 (1H, s), 7.08 (2H, d, J=8.4 Hz), 7.14 (2H, d,J=8.4 Hz), 7.45-7.55 (2H, m), 8.00-8.05 (2H, m).

EXAMPLE 113N-(7-(4-Methylphenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (4-methylphenyl)boronic acid, the titlecompound was obtained in the same manner as in Example 107. Yield: 68%.Melting point: 194-195° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.06 (3H, s), 2.26 (2H, s), 2.38 (3H, s), 2.86 (1H, septet, J=6.9 Hz),4.36 (1H, dd, J=4.9, 8.8 Hz), 4.55 (1H, dd, J=4.9, 9.3 Hz), 4.81 (1H,dd, J=8.8, 9.3 Hz), 6.50 (1H, s), 7.07 (2H, d, J=8.3 Hz), 7.11 (2H, d,J=8.3 Hz), 7.22 (4H, s).

EXAMPLE 114N-(3-(4-Isopropylphenyl)-7-(pyridin-3-yl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and pyridin-3-ylboronic acid, the title compoundwas obtained in the same manner as in Example 107. Yield: 32%. Meltingpoint: 142-144° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s),2.08 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.39 (1H, dd,J=5.0, 9.1 Hz), 4.58 (1H, dd, J=5.0, 9.1 Hz), 4.81 (1H, t, J=9.1 Hz),6.56 (1H, s), 7.09 (2H, d, J=8.2 Hz), 7.15 (2H, d, J=8.2 Hz), 7.26-7.38(1H, m), 7.67-7.72 (1H, m), 8.56-8.61 (2H, m).

EXAMPLE 115N-(3-(4-Isopropylphenyl)-7-(pyridin-4-yl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and pyridin-4-ylboronic acid, the title compoundwas obtained in the same as in Example 107.

Yield: 72%. Melting point: 150-152° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s),2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.39 (1H, dd,J=4.9, 8.8 Hz), 4.57 (1H, dd, J=4.9, 9.3 Hz), 4.81 (1H, t, J=9.0 Hz),6.53 (1H, s), 7.07 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1 Hz), 7.27 (2H,d, J=5.9 Hz), 8.65 (2H, d, J=5.9 Hz).

EXAMPLE 116(5-((3,3-Dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid

A solution ofN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(1.38 g, 3 mmol) obtained in Example 35 in THF solution (20 mL) wascooled to −72° C. To the reaction solution was added n-butyllithium (1.6M THF solution, 5.63 mL, 9 mmol) and the reaction mixture was stirredfor 30 minutes, and thereto was further added triisopropyl boronate(2.42 mL, 10.5 mmol). The reaction solution was warmed to roomtemperature over a period of 1 hour, treated with 1 N hydrochloric acid,and extracted with ethyl acetate. The extracts were washed withsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:methanol=9:1) to obtain 613 mg (yield:48%) of the title compound. Melting point: 151-153° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.26 (2H, s), 2.49 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.45-4.55 (2H,m), 4.87 (1H, t, J=9.0 Hz), 5.88 (2H, s), 6.49 (1H, s), 7.01 (2H, d,J=8.2 Hz), 7.11 (2H, d, J=8.2 Hz).

EXAMPLE 117N-(3-(4-Isopropylphenyl)-7-(pyridin-2-yl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-bromopyridine, the title compound wasobtained in the same manner as in Example 107.

Yield: 53%. Melting point: 198-200° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.04 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.37 (1H, dd,J=4.9, 9.0 Hz), 4.57 (1H, dd, J=4.9, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz),6.75 (1H, s), 7.05-7.13 (4H, m), 7.22-7.26 (1H, m), 7.43 (1H, d, J=7.7Hz), 7.74 (1H, td, J=7.7, 0.8 Hz), 8.69-8.73 (1H, m).

EXAMPLE 118N-(3-(4-Isopropylphenyl)-7-(5-methylpyridin-2-yl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-bromo-5-methylpyridine, the titlecompound was obtained in the same manner as in Example 107. Yield: 67%.Melting point: 228-229° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.01 (3H, s), 2.25 (2H, s), 2.37 (3H, s), 2.85 (1H, septet, J=6.9 Hz),4.36 (1H, dd, J=4.9, 9.0 Hz), 4.57 (1H, dd, J=4.9, 9.0 Hz), 4.81 (1H, t,J=9.0 Hz), 6.90 (1H, s), 7.09 (2H, d, J=8.3 Hz), 7.11 (2H, d, J=8.3 Hz),7.32 (1H, d, J=8.0 Hz), 7.53-7.58 (1H, m), 8.54 (1H, br s).

EXAMPLE 119N-(7-(6-Aminopyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-amino-6-bromopyridine, the titlecompound was obtained in the same manner as in Example 107. Yield: 68%.Melting point: 237-239° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.88 (3H, s),2.10 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.36 (1H, dd,J=4.9, 9.0 Hz), 4.54 (2H, brs), 4.56 (1H, dd, J=4.9, 9.0 Hz), 4.83 (1H,t, J=9.0 Hz), 6.45 (1H, d, J=8.2 Hz), 6.47 (1H, s), 6.77 (1H, d, J=7.4Hz), 7.08 (2H, d, J=8.6 Hz), 7.12 (2H, d, J=8.6 Hz), 7.50 (1H, dd,J=7.4, 8.2 Hz)

EXAMPLE 120N-(7-(3-Dimethylaminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 3-bromo-N,N-dimethylaniline, the titlecompound was obtained in the same manner as in Example 107. Yield: 77%.Melting point: 197-199° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.06 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 2.95 (6H, s),4.34-4.39 (1H, m), 4.53-4.58 (1H, m), 4.77 (1H, t, J=9.1 Hz), 6.50 (1H,s), 6.63-6.77 (3H, m), 7.06-7.16 (4H, m), 7.27-7.33 (1H, m).

EXAMPLE 121N-(7-(6-(Acetylamino)pyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(7-(6-aminopyridin-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(94.3 mg, 0.2 mmol) and triethylamine (0.042 mL, 0.3 mmol) in THF (1 mL)was added acetyl chloride (0.015 mL, 0.22 mmol) at 0° C. and theresulting mixture was stirred at room temperature for 1 hour. Thereaction solution was diluted with saturated sodium bicarbonate solutionand extracted with ethyl acetate. The extracts were washed withsaturated brine, dried over sodium sulfate, and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) to obtain 51 mg (yield: 50%)of the title compound. Melting point: 205-208° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.59 (3H, s),1.90 (3H, s), 2.07 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz),4.33-4.39 (1H, m), 4.57 (1H, dd, J=4.9, 9.3 Hz), 4.82 (1H, t, J=9.1 Hz),6.49 (1H, s), 7.03-7.18 (5H, m), 7.76 (1H, t, J=7.9 Hz), 7.99 (1H, br),8.14 (1H, d, J=7.9 Hz).

EXAMPLE 122N-(7-(3-Aminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(7-(3-nitrophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(2.50 g, 5 mmol) obtained in Example 109 and ammonium formate (1.26 g,20 mmol) in ethanol (50 mL) was added 10% palladium on carbon (watercontent: 50%, 0.25 g), and the resulting mixture was heated at 65° C.and stirred for 2 hours. The reaction solution was cooled to roomtemperature, the catalyst was filtered off, and the fitrate wasconcentrated under reduced pressure.

The residue was diluted with water and extracted with ethyl acetate. Theextracts were washed with saturated brine, dried over sodium sulfate,and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethyl acetate) to obtain2.15 g (yield: 92%) of the title compound. Melting point: 170-172° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.05 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.67 (2H, brs),4.37 (1H, dd, J=4.9, 9.0 Hz), 4.54 (1H, dd, J=4.9, 9.0 Hz), 4.77 (1H, t,J=9.0 Hz), 6.51 (1H, s), 6.63-6.73 (3H, m), 7.05-7.15 (4H, m), 7.19 (1H,dd, J=5.0, 5.8 Hz).

EXAMPLE 123N-(3-(4-Isopropylphenyl)-7-(3-propionylaminophenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-(3-aminophenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 122 and propionyl chloride, the title compound wasobtained in the same manner as in Example 121. Yield: 84%. Meltingpoint: 237-239° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.20-1.26 (9H, m), 1.91 (3H, s), 2.05(3H, s), 2.26 (2H, s), 2.37 (2H, q, J=7.4 Hz), 2.86 (1H, septet, J=6.9Hz), 4.35 (1H, dd, J=4.9, 8.5 Hz), 4.54 (1H, dd, J=4.9, 9.2 Hz), 4.77(1H, t, J=9.1 Hz), 6.50 (1H, s), 7.02-7.09 (3H, m), 7.13 (2H, d, J=8.0Hz), 7.24 (1H, br), 7.30-7.40 (2H, m), 7.63 (1H, br).

EXAMPLE 124N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(pyrimidin-5-yl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 5-bromopyrimidine, the title compoundwas obtained in the same manner as in Example 107. Yield: 77%. Meltingpoint: 167-169° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.94 (3H, s),2.12 (3H, s), 2.28 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.40 (1H, dd,J=4.9, 9.0 Hz), 4.58 (1H, dd, J=4.9, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz),6.53 (1H, s), 7.07 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 8.76 (2H,s), 9.18 (1H, s).

EXAMPLE 125N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(1,3-thiazol-2-yl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-bromo-1,3-thiazole, the titlecompound was obtained in the same manner as in Example 107. Yield: 64%.Melting point: 164-166° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.25 (3H, s), 2.27 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.46 (1H, dd,J=4.9, 9.0 Hz), 4.58 (1H, dd, J=4.9, 9.0 Hz), 4.90 (1H, t, J=9.0 Hz),6.72 (1H, s), 7.07 (2H, d, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 7.47 (1H,d, J=3.2 Hz), 7.93 (1H, d, J=3.2 Hz).

EXAMPLE 126N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(3-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 3-bromothiophene, the title compoundwas obtained in the same manner as in Example 107. Yield: 49%. Meltingpoint: 172-174° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.14 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.40 (1H, dd,J=4.9, 9.0 Hz), 4.55 (1H, dd, J=4.9, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz),6.51 (1H, s), 7.05-7.17 (5H, m), 7.26-7.43 (2H, m).

EXAMPLE 127N-(7-(1H-Imidazol-4-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 4-bromoimidazole, the title compoundwas obtained in the same manner as in Example 107. Yield: 48%. Meltingpoint: 277-279° C. (ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.28 (2H, s), 2.34 (3H, brs), 2.86 (1H, septet, J=6.9 Hz), 4.40-4.58(2H, m), 4.81-4.88 (1H, m), 6.50 (1H, s), 6.92 (1H, s), 7.06 (2H, d,J=8.3 Hz), 7.11 (2H, d, J=8.3 Hz), 7.21 (1H, br s), 7.68 (1H, s).

EXAMPLE 128N-(7-(3-Furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and 3-furylboronic acid, the title compound wasobtained in the same manner as in Example 107. Yield: 51%. Meltingpoint: 183-185° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.21 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.41 (1H, dd,J=8.5, 4.9 Hz), 4.55 (1H, dd, J=9.6, 4.9 Hz), 4.83 (1H, dd, J=8.5, 9.6Hz), 6.50 (1H, s), 6.57 (1H, d, J=1.9 Hz), 7.06 (2H, d, J=8.3 Hz), 7.12(2H, d, J=8.3 Hz), 7.48-7.50 (1H, m), 7.53-7.55 (1H, m).

EXAMPLE 129N-(7-(1H-Pyrrol-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid, the title compound was obtained in the same manner as inExample 107. Yield: 19%. Melting point: 188-190° C. (ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.27 (2H, s), 2.39 (3H, s), 2.86 (1H, septet, J=6.9 Hz), 4.45-4.50 (1H,m), 4.53-4.59 (1H, m), 4.87 (1H, t, J=8.6 Hz), 6.30-6.34 (1H, m), 6.42(1H, br), 6.53 (1H, s), 6.87 (1H, br), 7.05 (2H, d, J=8.0 Hz), 7.11 (2H,d, J=8.0 Hz), 9.32 (1H, br).

EXAMPLE 130N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromothiophene, the titlecompound was synthesized in the same manner as in Example 107. Yield:58%. Melting point: 155-156° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.91 (3H, s),2.16 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.41 (1H, dd,J=8.7, 5.1 Hz), 4.57 (1H, dd, J=9.3, 5.1 Hz), 4.84 (1H, t, J=10.8 Hz),6.50 (1H, br s), 7.00-7.16 (6H, m), 7.38 (1H, dd, J=5.1, 1.2 Hz).

EXAMPLE 131N-(7-(5-Acetyl-2-thienyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-acetyl-5-bromothiophene, the titlecompound was synthesized in the same manner as in Example 107. Yield:65%. Melting point: 157-158° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.19 (3H, s), 2.27 (2H, s), 2.57 (3H, s), 2.87 (1H, septet, J=6.9 Hz),4.43 (1H, dd, J=8.1, 4.8 Hz), 4.58 (1H, dd, J=9.9, 4.5 Hz), 4.85 (1H, t,J=9.0 Hz), 6.54 (1H, br s), 7.05-7.21 (5H, m), 7.71 (1H, d, J=3.9 Hz).

EXAMPLE 132N-(7-(5-Acetyl-3-thienyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-acetyl-4-bromothiophene, the titlecompound was synthesized in the same manner as in Example 107. Yield:62%. Melting point: 133-134° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.15 (3H, s), 2.27 (2H, s), 2.58 (3H, s), 2.87 (1H, septet, J=6.9 Hz),4.41 (1H, dd, J=8.7, 4.8 Hz), 4.58 (1H, dd, J=9.3, 5.1 Hz), 4.83 (1H, t,J=9.0 Hz), 6.56 (1H, br s), 7.08 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1Hz), 7.58 (1H, d, J=1.2 Hz), 7.74 (1H, d, J=1.2 Hz).

EXAMPLE 133N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(4-methyl-1,3-thiazol-2-yl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronicacid obtained in Example 116 and 2-bromo-4-methyl-1,3-thiazole, thetitle compound was synthesized in the same manner as in Example 107.Yield: 62%. Melting point: 240-241° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.22 (3H, s), 2.26 (2H, s), 2.53 (3H, s), 2.86 (1H, septet, J=6.9 Hz),4.44 (1H, dd, J=8.7, 5.4 Hz), 4.64 (1H, dd, J=9.3, 5.7 Hz), 4.90 (1H, t,J=9.0 Hz), 6.61 (1H, br s), 7.01 (1H, s), 7.07 (2H, d, J=8.1 Hz), 7.13(2H, d, J=8.1 Hz).

EXAMPLE 134(+)-N-((3R)-7-Hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of(+)-N-((3R)-3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(500 mg, 1.22 mmol) obtained in Example 52 in dichloromethane (20 mL)was added dropwise at −78° C. under an argon atmosphere boron tribromide(1.0 M dichloromethane solution, 3.0 mL, 3.0 mmol). The reactionsolution was warmed to room temperature, added to an aqueous saturatedsodium hydrogen carbonate solution, and extracted with ethyl acetate.The combined organic layers were washed with saturated brine, dried oversodium sulfate, filtered, and then concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of thetitle compound. Melting point: 202-203° C. (ethyl acetate-hexane).

[α]_(D) ²⁰=+79.00 (c=0.49, chloroform).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.80 (3H, s),2.14 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.46 (1H, dd,J=4.5, 8.7 Hz), 4.55 (1H, dd, J=4.5, 8.7 Hz), 4.86 (1H, t, J=8.7 Hz),4.89 (1H, br s), 6.49 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.12 (2H, d,J=8.1 Hz).

EXAMPLE 135N-(7-Hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 36, the title compound was synthesized in the samemanner as in Example 134. Yield: 78%. Melting point: 181-182° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.80 (3H, s),2.14 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 4.46 (1H, dd,J=4.5, 8.7 Hz), 4.55 (1H, dd, J=4.5, 8.7 Hz), 4.84 (1H, t, J=8.7 Hz),4.95 (1H, br s), 6.51 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d,J=8.1 Hz).

EXAMPLE 136N-(7-Ethoxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixed solution ofN-(7-hydroxy-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 135 (300 mg, 0.76 mmol), potassium carbonate (105mg, 0.76 mmol) and diethyl sulfate (117 mg, 0.76 mmol) in acetone (15mL) was refluxed with heating for 14 hours. Water was added to thereaction solution and the product was extracted with ethyl acetate. Thecombined organic layers were washed with saturated brine, dried oversodium sulfate, filtered, and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:2) to synthesize 378 mg (yield: 78%) of thetitle compound. Melting point: 174-175° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.37 (3H, t,J=7.2 Hz), 1.82 (3H, s), 2.16 (3H, s), 2.24 (2H, s), 2.86 (1H, septet,J=6.9 Hz), 4.07-4.20 (2H, m), 4.43-4.53 (2H, m), 4.85 (1H, t, J=8.1 Hz),6.47 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 137 tert-Butyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30, the title compound was synthesized inthe same manner as in Reference Example 59. Yield: 53%. Melting point:121-122° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.20-1.50 (9H, m), 1.87 (3H,s), 2.17 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 4.40 (1H, dd, J=4.5, 8.7Hz), 4.47-4.51 (1H, m), 4.80 (1H, t, J=8.7 Hz), 5.71 (1H, br s), 7.03(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 138 2,2,2-Trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

To a solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(1.48 g, 5 mmol) obtained in Reference Example 30 and triethylamine(0.22 mL, 1.61 mmol) in THF (15 mL) was added 2,2,2-trichloroethylchloroformate (0.76 mL, 5.5 mmol) at 0° C. and the reaction mixture wasstirred at room temperature for 1 hour. The reaction solution wasdiluted with water and extracted with ethyl acetate. The organic layerwas washed with 1 N hydrochloric acid and an aqueous saturated sodiumhydrogen carbonate solution, dried over sodium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=3:1) to obtain 2.19 g(yield: 93%) of the title compound. Melting point: 137-140° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.88 (3H, s), 2.10 (6H, s),2.86 (1H, septet, J=6.9 Hz), 4.38-4.45 (1H, m), 4.50-4.56 (1H, m),4.75-4.86 (3H, m), 6.15 (1H, s), 7.03 (2H, d, J=8.0 Hz), 7.11 (2H, d,J=8.0 Hz).

EXAMPLE 139 2,2,2-Trichloroethyl(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 328, the title compound was synthesized inthe same manner as in Example 138. Yield: 82%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz), 1.88(3H, s), 2.22 (3H, s), 2.66 (2H, q, J=7.5 Hz), 2.86 (1H, septet, J=6.9Hz), 4.42 (1H, dd, J=5.1, 8.7 Hz), 4.53 (1H, dd, J=4.8, 9.3 Hz),4.75-4.90 (3H, m), 6.15 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.13 (2H, d,J=8.1 Hz).

EXAMPLE 140 2,2,2-Trichloroethyl(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 327, the title compound was synthesized inthe same manner as in Example 138. Yield: 68%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.86 (3H, s), 2.19 (3H, s),2.86 (1H, septet, J=6.9 Hz), 3.90 (3H, s), 4.45-4.58 (2H, m), 4.77-4.92(3H, m), 6.15 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1Hz).

EXAMPLE 141 2,2,2-Trichloroethyl(7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propan-1-olobtained in Reference Example 322, the title compound was synthesized inthe same manner as in Example 138. Yield: 51%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.85-2.05 (5H, m), 2.21 (3H,s), 2.70-2.92 (3H, m), 4.27 (2H, t, J=6.6 Hz), 4.40 (1H, dd, J=5.1, 8.7Hz), 4.52 (1H, dd, J=5.1, 9.1 Hz), 4.77-4.92 (3H, m), 6.15 (1H, br s),7.02 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 1H unidentified.

EXAMPLE 142 2,2,2-Trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 329, the title compound was synthesized inthe same manner as in Example 138. Yield: 89%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.95 (3H, s), 2.10 (3H, s),2.87 (1H, septet, J=6.9 Hz), 4.38 (1H, dd, J=5.1, 8.7 Hz), 4.56 (1H, dd,J=4.8, 9.3 Hz), 4.75-4.90 (3H, m), 6.20 (1H, br s), 7.08 (2H, d, J=8.1Hz), 7.14 (2H, d, J=8.1 Hz), 7.24-7.50 (5H, m).

EXAMPLE 143N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)pyrrolidin-1-carboxamide

To a solution of 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate(353 mg, 0.75 mmol) obtained in Example 138 and pyrrolidine (0.076 mL,0.9 mmol) in dimethylsulfoxide (5 mL) was added diisopropylethylamine(0.13 mL, 0.75 mmol) at room temperature, and the resulting mixture washeated at 50° C. and reacted for 16 hours. The reaction solution wascooled to room temperature and poured into water, and the product wasextracted with ethyl acetate. The organic layer was washed with anaqueous saturated sodium hydrogen carbonate solution, dried over sodiumsulfate, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane:ethylacetate=1:1) to obtain 130 mg (yield: 44%) of the title compound.Melting point: 186-188° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.87 (3H, s), 1.92-2.00 (4H,m), 2.17 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.43 (4H,br), 4.38-4.43 (1H, m), 4.48-4.53 (1H, m), 4.78-4.84 (1H, m), 5.43 (1H,s), 7.04 (2H, d, J=8.2 Hz), 7.10 (2H, d, J=8.2 Hz).

EXAMPLE 144N,N-Diethyl-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and diethylamine, the title compound wasobtained in the same manner as in Example 143.

Yield: 68%. Melting point: 79-81° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.18-1.23 (12H, m), 1.86 (3H, s), 2.15 (3H, s), 2.17(3H, s), 2.85 (1H, septet, J=7.0 Hz), 3.31-3.40 (4H, m), 4.38-4.43 (1H,m), 4.48-4.54 (1H, m), 4.80 (1H, t, J=8.8 Hz), 5.54 (1H, s), 7.04 (2H,d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 145N-(2-Hydroxyethyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 2-hydroxyethylamine, the title compound wasobtained in the same manner as in Example 143.

Yield: 89%. Melting point: 186-188° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.19 (3H, s),2.20 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.23 (1H, br), 3.32 (2H, br),3.64 (2H, br), 4.43-4.48 (1H, m), 4.50-4.56 (1H, m), 4.65 (1H, br), 4.85(1H, t, J=8.8 Hz), 5.64 (1H, br), 7.03 (2H, d, J=8.1 Hz), 7.14 (2H, d,J=8.1 Hz).

EXAMPLE 146N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(2-methoxyethyl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 2-methoxyethylamine, the title compound wassynthesized in the same manner as in Example 143. Yield: 58%. Meltingpoint: 172-173° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.88 (3H, s), 2.18 (6H, s),2.86 (1H, septet, J=6.9 Hz), 3.05-3.44 (7H, m), 4.40-4.63 (3H, m), 4.85(1H, t, J=9.0 Hz), 5.53 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.13 (2H, d,J=8.1 Hz).

EXAMPLE 147N-(2-(Dimethylamino)ethyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 2-(dimethylamino)ethylamine, the titlecompound was synthesized in the same manner as in Example 143. Yield:54%. Melting point: 133-134° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s), 2.10 (6H, br s),2.19 (6H, s), 2.28 (2H, br s), 2.87 (1H, septet, J=6.9 Hz), 3.10-3.35(2H, m), 4.44 (1H, dd, J=8.7, 4.8 Hz), 4.53 (1H, dd, J=9.0, 4.5 Hz),4.69 (1H, br s), 4.85 (1H, t, J=9.0 Hz), 5.70 (1H, br s), 7.03 (2H, d,J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz).

EXAMPLE 148N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(2-hydroxyethyl)urea

Using 2,2,2-trichloroethyl(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 139 and 2-aminoethanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 57%. Meltingpoint: 147-148° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.15 (3H, t, J=7.5 Hz), 1.22 (6H, d, J=6.9 Hz), 1.89(3H, s), 2.23 (3H, s), 2.25-2.75 (2H, m), 2.87 (1H, septet, J=6.9 Hz),3.17-3.40 (3H, m), 3.44-3.70 (2H, m), 4.40-4.58 (2H, m), 4.68 (1H, brs), 4.85 (1H, t, J=8.4 Hz), 5.71 (1H, br s), 7.03 (2H, d, J=7.8 Hz),7.14 (2H, d, J=7.8 Hz).

EXAMPLE 149N-(2-Hydroxyethyl)-N′-(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 140 and 2-aminoethanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 59%. Meltingpoint: 127-129° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.86 (3H, s), 2.19 (3H, s),2.87 (1H, septet, J=6.9 Hz), 3.17-3.40 (3H, m), 3.44-3.72 (2H, m), 3.91(3H, s), 4.40-4.90 (4H, m), 5.83 (1H, br s), 7.03 (2H, d, J=7.8 Hz),7.14 (2H, d, J=7.8 Hz).

EXAMPLE 150N-(2-Hydroxyethyl)-N′-(7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 141 and 2-aminoethanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 53%. Meltingpoint: 153-154° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.69-1.94 (5H, m), 2.07-2.40(4H, m), 2.72-2.90 (3H, m), 3.00-3.40 (3H, m), 3.42-3.75 (4H, m),4.41-4.70 (3H, m), 4.85 (1H, t, J=8.4 Hz), 5.63 (1H, br s), 7.00 (2H, d,J=7.8 Hz), 7.13 (2H, d, J=7.8 Hz).

EXAMPLE 151N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-propylurea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 1-propylamine, the title compound wassynthesized in the same manner as in Example 143. Yield: 53%. Meltingpoint: 177-178° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 0.81 (3H, br s), 1.22 (6H, d, J=6.9 Hz), 1.41 (2H, brs), 1.87 (3H, s), 2.19 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 3.14 (2H,br s), 4.18 (1H, br s), 4.45 (1H, dd, J=8.4, 4.8 Hz), 4.53 (1H, dd,J=9.3, 4.8 Hz), 4.85 (1H, t, J=9.0 Hz), 5.51 (1H, br s), 7.01 (2H, d,J=8.1 Hz), 7.12 (2H, d, J=7.8 Hz).

EXAMPLE 152N-(2-Hydroxyethyl)-N′-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 142 and 2-aminoethanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 59%. Meltingpoint: 152-155° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.71 (2H, br s), 1.88 (3H, s),2.19 (6H, s), 2.87 (1H, septet, J=6.9 Hz), 3.15-3.40 (3H, m), 3.42-3.67(2H, m), 4.35-4.58 (3H, m), 4.85 (1H, t, J=8.7 Hz), 5.64 (1H, br s),7.04 (2H, br s), 7.14 (2H, d, J=7.8 Hz).

EXAMPLE 153N-(3-Hydroxypropyl)-N′-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 142 and 3-amino-1-propanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 65%. Meltingpoint: 145-146° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.40-1.60 (4H, m), 1.88 (3H,br s), 2.19 (6H, s), 2.87 (1H, septet, J=6.9 Hz), 3.00-3.70 (5H, m),4.36 (1H, br s), 4.45 (1H, dd, J=8.4, 4.8 Hz), 4.52 (1H, dd, J=8.7, 4.8Hz), 4.85 (1H, t, J=9.0 Hz), 5.50 (1H, br s), 7.02 (2H, d, J=8.1 Hz),7.13 (2H, d, J=8.1 Hz).

EXAMPLE 154N-(3-Hydroxypropyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 3-amino-1-propanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 33%. Meltingpoint: 185-186° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.97 (3H, s), 2.12 (3H, s),2.88 (1H, septet, J=6.9 Hz), 3.24-3.78 (5H, m), 4.43 (1H, dd, J=9.0, 4.8Hz), 4.57 (1H, dd, J=9.1, 4.5 Hz), 4.72-4.90 (2H, m), 5.66 (1H, br s),7.09 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz), 7.28-7.50 (5H, m).

EXAMPLE 155N-(4-Hydroxybutyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 4-amino-1-butanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 28%. Meltingpoint: 145-146° C. (ethanol-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.40-1.60 (4H, m), 1.88 (3H,s), 2.19 (6H, s), 2.87 (1H, septet, J=6.9 Hz), 3.00-3.30 (2H, m),3.40-3.71 (2H, m), 4.36 (1H, br s), 4.45 (1H, dd, J=8.4, 4.8 Hz), 4.52(1H, dd, J=8.7, 4.8 Hz), 4.85 (1H, t, J=9.0 Hz), 5.50 (1H, br s), 7.02(2H, d, J=7.8 Hz), 7.13 (2H, d, J=7.8 Hz), 1H unidentified.

EXAMPLE 156N-(2-Hydroxy-1,1-dimethylethyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 2-amino-2-methyl-1-propanol, the titlecompound was synthesized in the same manner as in Example 143. Yield:39%. Melting point: 157-158° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.00-1.30 (12H, m), 1.86 (3H, s), 2.18 (3H, s), 2.20(3H, s), 2.86 (1H, septet, J=6.9 Hz), 3.42-3.60 (2H, m), 4.07-4.30 (1H,m), 4.45 (1H, dd, J=8.7, 4.8 Hz), 4.54 (1H, dd, J=9.0, 5.1 Hz), 4.87(1H, t, J=9.0 Hz), 5.38-5.62 (2H, m), 6.94-7.05 (2H, m), 7.12 (2H, d,J=8.1 Hz)

EXAMPLE 157N-(2-Hydroxy-1,1-dimethylethyl)-N′-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 142 and 2-amino-2-methyl-1-propanol, the titlecompound was synthesized in the same manner as in Example 143. Yield:49%. Melting point: 181-182° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.00-1.37 (12H, m), 1.95 (3H, s), 2.11 (3H, s), 2.88(1H, septet, J=6.9 Hz), 3.42-3.60 (2H, m), 4.10-4.47 (2H, m), 4.59 (1H,dd, J=9.3, 4.8 Hz), 4.85 (1H, t, J=9.0 Hz), 5.34 (1H, br s), 5.61 (1H,br s), 7.06 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz), 7.26-7.50 (5H,m).

EXAMPLE 158N-(3-Hydroxy-2,2-dimethylpropyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and 3-amino-2,2-methyl-1-propanol, the titlecompound was synthesized in the same manner as in Example 143. Yield:61%. Melting point: 117-118° C. (ethanol-hexane).

¹H-NMR (CDCl₃) δ: 0.48-0.80 (6H, m), 1.19 (6H, d, J=6.9 Hz), 1.89 (3H,s), 2.20 (6H, s), 2.57-3.35 (5H, m), 4.22-4.67 (4H, m), 4.88 (1H, t,J=9.0 Hz), 5.64 (1H, d, J=20.7 Hz), 7.02 (2H, d, J=6.6 Hz), 7.10-7.18(2H, m).

EXAMPLE 159N-(3-Hydroxy-2,2-dimethylpropyl)-N′-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 142 and 3-amino-2,2-methyl-1-propanol, the titlecompound was synthesized in the same manner as in Example 143. Yield:77%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 0.48-0.85 (6H, m), 1.22 (6H, d, J=6.9 Hz), 1.97 (3H,s), 2.11 (3H, s), 2.57-3.35 (5H, m), 4.22-4.67 (4H, m), 4.84 (1H, t,J=9.0 Hz), 5.72 (1H, d, J=21.6 Hz), 7.07 (2H, d, J=8.1 Hz), 7.14 (2H, d,J=8.1 Hz), 7.27-7.45 (5H, m).

EXAMPLE 160N-(2-Hydroxypropyl)-N′-(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 142 and 1-amino-2-propanol, the title compound wassynthesized in the same manner as in Example 143. Yield: 58%. Meltingpoint: 171-182° C. (ethanol-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (3H, br s), 1.23 (6H, d, J=6.9 Hz), 1.97 (3H, s),2.12 (3H, s), 2.60-3.50 (4H, m), 3.83 (1H, br s), 4.42 (1H, dd, J=9.0,4.5 Hz), 4.56 (1H, dd, J=9.3, 4.8 Hz), 4.74 (1H, br s), 4.83 (1H, t,J=9.0 Hz), 5.65 (1H, br s), 7.07 (2H, d, J=6.6 Hz), 7.15 (2H, d, J=6.6Hz), 7.27-7.48 (5H, m).

EXAMPLE 161N-(3-(4-Isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothiophene-5-amineobtained in Reference Example 291, the title compound was synthesized inthe same manner as in Example 1. Yield: 81%. Melting point: 151-152° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.21 (3H, s), 2.24 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 3.14 (1H, dd,J=11.4, 1.8 Hz), 3.92 (1H, dd, J=11.4, 8.4 Hz), 4.64 (1H, d, J=7.8 Hz),6.51 (1H, br s), 7.02 (2H, d, J=8.1 Hz), 7.03 (1H, s), 7.09 (2H, d,J=8.1 Hz).

EXAMPLE 162N-(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamideobtained in Example 161, the title compound was synthesized in the samemanner as in Reference Example 259. Yield: 55%. Melting point: 207-208°C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.24 (2H, s), 2.32 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.13 (1H, dd,J=11.1, 2.1 Hz), 3.92 (1H, dd, J=11.1, 8.7 Hz), 4.83 (1H, d, J=8.1 Hz),6.61 (1H, br s), 7.03 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 163N-(7-Formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamideobtained in Example 161, the title compound was synthesized in the samemanner as in Example 20. Yield: 65%. Melting point: 134-140° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.99 (3H, s),2.29 (2H, s), 2.55 (3H, s), 2.84 (1H, septet, J=6.9 Hz), 3.16 (1H, dd,J=11.4, 1.8 Hz), 3.83 (1H, dd, J=11.4, 9.0 Hz), 4.64 (1H, d, J=9.0 Hz),6.64 (1H, br s), 7.00 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz), 10.5(1H, s).

EXAMPLE 164N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

To methylmagnesium bromide (1.0 M, THF solution, 10 mL, 10 mmol) wasadded at 0° C.N-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide(600 mg, 1.42 mmol) obtained in Example 163 and the reaction solutionwas stirred at room temperature for 1 hour. The reaction solution wasadded to water and the product was extracted with ethyl acetate. Theorganic layer was washed with 1 N hydrochloric acid and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. To a mixture of the obtained residue in trifluoroacetic acid(3 mL) was added with ice-cooling triethylsilane (1.0 mL) and theresulting mixture was stirred at room temperature for 30 minutes. Afterthe reaction solution was concentrated under reduced pressure, to theresidue was added an aqueous saturated sodium hydrogen carbonatesolution and the aqueous layer was made alkaline, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain345 mg (yield: 57%) of the title compound. Melting point: 172-173° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.18 (3H, t, J=7.8 Hz), 1.21 (6H, d,J=6.9 Hz), 1.89 (3H, s), 2.20 (3H, s), 2.26 (2H, s), 2.66 (2H, q, J=7.8Hz), 2.85 (1H, septet, J=6.9 Hz), 3.12 (1H, dd, J=11.4, 1.8 Hz), 3.87(1H, dd, J=11.4, 8.7 Hz), 4.69 (1H, d, J=8.7 Hz), 6.51 (1H, br s), 7.03(2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 165N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-propyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

UsingN-(7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamideobtained in Example 163 and ethylmagnesium bromide, the title compoundwas synthesized in the same manner as in Example 164. Yield: 22%.Melting point: 159-160° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.02 (3H, t, J=7.5 Hz), 1.12 (9H, s), 1.21 (6H, d,J=6.9 Hz), 1.50-1.70 (2H, m), 1.89 (3H, s), 2.18 (3H, s), 2.26 (2H, s),2.61 (2H, t, J=6.9 Hz), 2.85 (1H, septet, J=6.9 Hz), 3.11 (1H, d, J=14.4Hz), 3.86 (1H, dd, J=14.4, 8.4 Hz), 4.69 (1H, dd, J=8.4 Hz), 6.53 (1H,br s), 7.03 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 166N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamideobtained in Example 161, the title compound was synthesized in the samemanner as in Example 38. Yield: 69%. Melting point: 218-219° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.94 (3H, s),2.20 (3H, s), 2.27 (2H, s), 2.57 (3H, s), 2.85 (1H, septet, J=6.9 Hz),3.15 (1H, dd, J=11.1, 1.8 Hz), 3.87 (1H, dd, J=11.1, 8.4 Hz), 4.66 (1H,d, J=8.4 Hz), 6.63 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.11 (2H, d,J=8.1 Hz).

EXAMPLE 167N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxido-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

To a mixture ofN-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide(225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogencarbonate (65 mg, 1.01 mmol) in dichloromethane (10 mL) was addedm-chloroperbenzoic acid

(124 mg, 0.716 mmol) at 0° C. and the resulting mixture was stirred atroom temperature for two hours. To reaction solution was added anaqueous sodium hydrogensulfite solution, the organic layer separated,and the aqueous layer was extracted with dichloromethane. The combinedorganic layers were washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1) to obtain 50 mg (yield: 22%) of the titlecompound. Melting point: 195-196° C. (diethyl ether-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.18 (3H, t, J=7.8 Hz), 1.21 (6H, d,J=6.9 Hz), 1.72 (3H, s), 2.18 (3H, s), 2.26 (1H, d, J=13.2 Hz), 2.32(1H, d, J=13.2 Hz), 2.87-2.98 (2H, m), 3.04-3.17 (1H, m), 3.26 (1H, dd,J=14.4, 7.2 Hz), 3.55 (1H, dd, J=13.8, 7.2 Hz), 5.10 (1H, d, J=6.6 Hz),6.90 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 7.82 (1H, br s).

EXAMPLE 168N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxido-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

To a mixture ofN-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide(960 mg, 2.19 mmol) obtained in Example 166 and sodium hydrogencarbonate (276 mg, 3.29 mmol) in dichloromethane (20 mL) was addedm-chloroperbenzoic acid (530 mg, 3.07 mmol) at 0° C. and the resultingmixture was stirred at room temperature for two hours. To reactionsolution was added an aqueous sodium hydrogensulfite solution, theorganic layer separated, and the aqueous layer was extracted withdichloromethane. The combined organic layers were washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (ethyl acetate) to obtain 123 mg (yield: 12%) ofthe title compound as a low polarity isomer. Melting point: 214-216° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.98 (3H, s),2.20 (3H, s), 2.29 (2H, s), 2.71 (3H, s), 2.85 (1H, septet, J=6.9 Hz),3.15 (1H, dd, J=14.4, 2.1 Hz), 3.70 (1H, dd, J=14.4, 8.7 Hz), 4.72 (1H,d, J=8.7. Hz), 6.81 (1H, br s), 7.12 (2H, d, J=8.1 Hz), 7.21 (2H, d,J=8.1 Hz).

EXAMPLE 169N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxido-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

The residue treated in the same manner as described in the Example 168was purified by silica gel column chromatography (ethyl acetate) toobtain 274 mg (yield: 28%) of the title compound as a high polarityisomer. Melting point: 214-215° C. (hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.84 (3H, s),2.20 (3H, s), 2.30 (2H, s), 2.65 (3H, s), 2.86 (1H, septet, J=6.9 Hz),3.30-3.40 (1H, m), 3.56 (1H, dd, J=13.2, 7.5 Hz), 5.07 (1H, d, J=6.3Hz), 6.90 (2H, d, J=8.1 Hz), 7.13 (2H, d, J=8.1 Hz), 7.56 (1H, br s).

EXAMPLE 170N-(7-Bromo-3-(4-isopropylphenyl)-4,6-dimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

To a mixture ofN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide(560 mg, 1.41 mmol) obtained in Example 161 and iron powder (5.2 mg,0.094 mmol) in dichloromethane (10 mL) was added bromine (225 mg, 1.41mmol) at 0° C. and the resulting mixture was stirred at the sametemperature for 1 hour. Water was poured into the reaction mixture andthe product was extracted with ethyl acetate. The extracts were washedwith an aqueous sodium hydrogen carbonate solution and water, dried overmagnesium sulfate, filtered, and concentrated under reduced pressure. Toa mixture of the obtained residue and sodium hydrogen carbonate (150 mg,1.79 mmol) in dichloromethane (5 mL) was added m-chloroperbenzoic acid(161 mg, 1.01 mmol) at 0° C. and the resulting mixture was stirred atroom temperature for 1 hour. To the reaction solution was added anaqueous sodium hydrogensulfite solution, the organic layer wasseparated, and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane ethyl acetate=3:1) to obtain 393 mg (yield: 55%)of the title compound. Melting point: 211-213° C. (hexane-ethylacetate).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.28 (2H, s), 2.36 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.47 (1H, dd,J=13.8, 2.4 Hz), 3.95 (1H, dd, J=13.8, 9.6 Hz), 4.65 (1H, d, J=9.6 Hz),7.00 (2H, d, J=8.1 Hz), 7.07 (1H, br s), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 171N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

To a mixture of the diastereo mixture ofN-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-1-oxide-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide(540 mg, 1.19 mmol) obtained in Examples 168 and 169, and sodiumhydrogen carbonate (150 mg, 1.79 mmol) in dichloromethane (5 mL) wasadded m-chloroperbenzoic acid (287 mg, 1.67 mmol) at 0° C. and theresulting mixture was stirred at room temperature for 2 hours. To thereaction solution was added an aqueous sodium hydrogensulfite solution,the organic layer was separated, and the aqueous layer was extractedwith dichloromethane. The combined organic layers were washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain320 mg (yield: 57%) of the title compound. Melting point: 184-186° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.07 (3H, s), 2.32 (2H, s), 2.68 (3H, s), 2.86 (1H, septet, J=6.9 Hz),3.42 (1H, dd, J=14.4, 2.4 Hz), 3.86 (1H, dd, J=14.4, 9.3 Hz), 4.71 (1H,dd, J=9.3, 2.4 Hz), 7.00-7.21 (5H, m).

EXAMPLE 172N-(7-Ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-1,1-dioxido-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide

To a mixture ofN-(7-ethyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide(225 mg, 0.512 mmol) obtained in Example 164 and sodium hydrogencarbonate (250 mg, 0.590 mmol) in dichloromethane (20 mL) was addedm-chloroperbenzoic acid (283 mg, 1.65 mmol) at 0° C. and the resultingmixture was stirred at room temperature for 2 hours. To the reactionsolution was added an aqueous sodium hydrogensulfite solution, theorganic layer was separated, and the aqueous layer was extracted withdichloromethane. The combined organic layers were washed with water andsaturated brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=4:1) to obtain 74 mg (yield:28%) of the title compound. Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.29 (3H, t,J=7.2 Hz), 1.86 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.84 (1H, septet,J=6.9 Hz), 3.07 (2H, q, J=7.8 Hz), 3.12 (1H, d, J=13.5 Hz), 3.87 (1H,dd, J=13.5, 9.6 Hz), 4.66 (1H, d, J=8.7 Hz), 6.86 (1H, br s), 7.01 (2H,d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz).

EXAMPLE 173N-(3-(3-Formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixed solution ofN-(3-(3-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(910 mg, 2.15 mmol) obtained in Example 73 and pyridiniump-toluenesulfonic acid (25 mg) in acetone (20 mL)-water (1.5 mL) wasrefluxed with heating for 30 minutes. The reaction solution was dilutedwith ethyl acetate, washed with an aqueous saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure to obtain 784 mg (yield: 96%)of the title compound. Melting point: 178-179° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.83 (3H, s), 2.16 (3H, s), 2.21 (3H,s), 2.25 (2H, s), 4.41 (1H, dd, J=4.5, 9.0 Hz), 4.64 (1H, dd, J=4.5, 9.0Hz), 4.87 (1H, t, J=9.0 Hz), 6.52 (1H, br s), 7.39-7.48 (2H, m), 7.66(1H, s), 7.72-7.76 (1H, m), 9.97 (1H, s).

EXAMPLE 174N-(3-(4-Formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-(1,3-dioxolan-2-yl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 82, the title compound was synthesized in the samemanner as in Example 173. Yield: 95%. Melting point: 195-196° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.83 (3H, s), 2.16 (3H, s), 2.19 (3H,s), 2.25 (2H, s), 6.51 (1H, br s), 7.31 (2H, d, J=8.4 Hz), 7.80 (2H, d,J=8.4 Hz), 9.97 (1H, s).

EXAMPLE 175N-(3-(4-(1-Hydroxyethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 174 and methylmagnesium bromide, the title compoundwas synthesized in the same manner as Example 22.

Yield: 93%. Melting point: 144-145° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.47 (3H, d, J=6.3 Hz), 1.78 (1H, br s),1.83 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 4.39 (1H, dd,J=4.5, 9.0 Hz), 4.54 (1H, dd, J=4.5, 9.0 Hz), 4.79-4.90 (2H, m), 6.50(1H, br s), 7.10 (2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz).

EXAMPLE 176N-(3-(4-Acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-(1-hydroxyethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 175, the title compound was synthesized in the samemanner as in Example 32. Yield: 65%. Melting point: 181-182° C.(THF-diisopropyl ether).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.82 (3H, s), 2.16 (3H, s), 2.19 (3H,s), 2.25 (2H, s), 2.57 (3H, s), 4.40 (1H, dd, J=4.5, 9.0 Hz), 4.61 (1H,dd, J=4.5, 9.0 Hz), 4.86 (1H, t, J=9.0 Hz), 6.51 (1H, br s), 7.23 (2H,d, J=8.4 Hz), 7.87 (2H, d, J=8.4 Hz).

EXAMPLE 177 Ethyl(2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate

To a solution of sodium hydride (a 60% dispersion in liquid paraffin, 79mg, 1.98 mmol) in DMF (10 mL) was added dropwise at 0° C. under an argonatmosphere ethyl diethylphosphonoacetate (444 mg, 1.98 mmol) and themixture was stirred for 30 minutes. To the reaction solution was addeddropwise at 0° C. a solution ofN-(3-(3-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(684 mg, 1.80 mmol) obtained in Example 173 in DMF (5 mL) and themixture was stirred for 30 minutes. The reaction solution was warmed toroom temperature, was added to water and the product was extracted withethyl acetate-THF. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, filtered, and thenconcentrated under reduced pressure to obtain 750 mg (yield: 93%) of thetitle compound. Melting point: 199-200° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.33 (3H, t, J=7.5 Hz), 1.83 (3H, s),2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 4.27 (2H, q, J=7.5 Hz), 4.39(1H, dd, J=4.5, 9.0 Hz), 4.54 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t,J=9.0 Hz), 6.38 (1H, d, J=15.3 Hz), 6.50 (1H, br s), 7.14 (1H, d, J=7.5Hz), 7.24-7.31 (2H, m), 7.37 (1H, d, J=7.5 Hz), 7.61 (1H, d, J=15.3 Hz).

EXAMPLE 178 Ethyl(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate

UsingN-(3-(4-formylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 174, the title compound was synthesized in the samemanner as in Example 177. Yield: 81%. Melting point: 176-177° C. (ethylacetate).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.33 (3H, t, J=6.9 Hz), 1.84 (3H, s),2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 4.26 (2H, q, J=6.9 Hz), 4.40(1H, dd, J=4.5, 9.0 Hz), 4.57 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t,J=9.0 Hz), 6.38 (1H, d, J=13.8 Hz), 6.51 (1H, br s), 7.15 (2H, d, J=8.1Hz), 7.43 (2H, d, J=8.1 Hz), 7.64 (1H, d, J=13.8 Hz).

EXAMPLE 179 Ethyl(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)but-2-enoate

UsingN-(3-(4-acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 176, the title compound was obtained in the samemanner as in Example 177. Yield: 75%. Melting point: 179-180° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.31 (3H, t, J=7.2 Hz), 1.84 (3H, s),2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.54 (3H, s), 4.20 (2H, q,J=7.2 Hz), 4.40 (1H, dd, J=4.5, 9.0 Hz), 4.56 (1H, dd, J=4.5, 9.0 Hz),4.84 (1H, t, J=9.0 Hz), 6.09 (1H, s), 6.49 (1H, s), 7.12 (2H, d, J=8.4Hz), 7.37 (2H, d, J=8.4 Hz).

EXAMPLE 180 Ethyl3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)propanoate

A mixed solution of ethyl(2E)-3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylate(400 mg, 0.89 mmol) obtained in Example 177 and 10% palladium on carbon(water content: 50%, 40 mg) in ethanol (3 mL)-ethyl acetate (5 mL) wasstirred at room temperature for 2 hours under a hydrogen atmosphere. Thereaction solution was filtered through celite and the filtrate wasconcentrated under reduced pressure to obtain 326 mg (yield: 81%) of thetitle compound. Melting point: 136-138° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (3H, t, J=7.2 Hz), 1.82 (3H, s),2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.57 (2H, t, J=7.8 Hz), 2.89(2H, t, J=7.8 Hz), 4.27 (2H, q, J=7.5 Hz), 4.39 (1H, dd, J=4.5, 9.0 Hz),4.54 (1H, dd, J=4.5, 9.0 Hz), 4.84 (1H, t, J=9.0 Hz), 6.50 (1H, br s),7.14 (1H, d, J=7.5 Hz), 7.24-7.31 (1H, t, J=7.5 Hz), 7.37 (1H, d, J=7.5Hz), 7.61 (1H, d, J=15.3 Hz).

EXAMPLE 181 Ethyl3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)propanoate

Using ethyl(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)acrylateobtained in Example 178, the title compound was synthesized in the samemanner as in Example 180. Yield: 84%. Melting point: 103-105° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (3H, t, J=6.9 Hz), 1.82 (3H, s),2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.58 (2H, t, J=7.8 Hz), 2.90(2H, t, J=7.8 Hz), 4.11 (2H, q, J=6.9 Hz), 4.38 (1H, dd, J=4.8, 9.0 Hz),4.51 (1H, dd, J=4.8, 9.0 Hz), 4.81 (1H, t, J=9.0 Hz), 6.49 (1H, br s),7.03 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz).

EXAMPLE 182 Ethyl3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoate

Using ethyl(2E)-3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)but-2-enoateobtained in Example 179, the title compound was synthesized in the samemanner as in Example 180. Yield: 76%. Melting point: 100-101° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.17 (3H, t, J=7.2 Hz), 1.26 (3H, d,J=6.6 Hz), 1.83 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s),2.44-2.60 (2H, m), 3.18-3.30 (1H, m), 4.11 (2H, q, J=7.2 Hz), 4.39 (1H,dd, J=4.8, 9.0 Hz), 4.52 (1H, dd, J=4.8, 9.0 Hz), 4.81 (1H, t, J=9.0Hz), 6.49 (1H, br s), 7.05 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz).

EXAMPLE 183N-(3-(4-Acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(1.0 g, 2.62 mmol) obtained in Example 72 in dichloromethane (20 mL) wasadded at −50° C. under an argon atmosphere aluminum chloride (769 mg,5.77 mmol) and the resulting mixture was stirred for 10 minutes. To thereaction solution was added dropwise at the same temperature acetylchloride (0.62 mL, 8.65 mmol and the resulting mixture was warmed toroom temperature. The reaction solution was added to water and theproduct was extracted with ethyl acetate. The combined organic layerswere washed with an aqueous saturated sodium hydrogen carbonatesolution, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to obtain 993 mg (yield: 89%) of the title compound.Melting point: 131-133° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.84 (3H, s), 2.15 (3H, s), 2.17 (3H,s), 2.26 (2H, s), 2.58 (3H, s), 3.84 (3H, s), 4.39 (1H, dd, J=4.8, 9.0Hz), 4.58 (1H, dd, J=4.8, 9.0 Hz), 4.85 (1H, t, J=9.0 Hz), 6.54 (1H, brs), 6.72 (1H, s), 6.76 (1H, d, J=8.1 Hz), 7.65 (1H, d, J=8.1 Hz).

EXAMPLE 184N-(3-(4-Isopropenyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of potassium tert-butoxide (818 mg, 7.29 mmol) in toluene(45 mL) was added methyl triphenylphosphonium iodide (2.94 g, 7.29 mmol)and the resulting mixture was stirred at 120° C. for 1 hour under anargon atmosphere. To the reaction solution was addedN-(3-(4-acetyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(2.32 g, 5.48 mmol) obtained in Example 183 and the resulting mixturewas stirred at 120° C. for 2 hours. Water was added to the reactionsolution, the organic layer was separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=2:3) to obtain 1.93 g (yield: 84%) of the titlecompound. Melting point: 186-187° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.87 (3H, s), 2.08 (3H, s), 2.15 (3H,s), 2.17 (3H, s), 2.26 (2H, s), 3.76 (3H, s), 4.42 (1H, dd, J=4.8, 9.0Hz), 4.54 (1H, dd, J=4.8, 9.0 Hz), 4.83 (1H, t, J=9.0 Hz), 5.03 (1H, s),5.11 (1H, s), 6.51 (1H, br s), 6.64-6.67 (2H, m), 7.60 (1H, d, J=7.5Hz).

EXAMPLE 185N-(3-(4-Isopropyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixed solution ofN-(3-(4-isopropenyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(1.93 g, 4.58 mmol) obtained in Example 184 and 10% palladium on carbon(water content: 50%, 193 mg) in ethanol (10 mL) was stirred at roomtemperature for 2 hours under a hydrogen atmosphere. The catalyst wasfiltered and the filtrate was concentrated to give 1.80 g (yield: 93%)of the title compound. Melting point: 170-171° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.17 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.04 (3H, s), 2.14 (3H, s), 2.25 (2H, s), 3.24 (1H, septet, J=6.9 Hz),3.75 (3H, s), 4.42 (1H, dd, J=5.1, 9.0 Hz), 4.52 (1H, dd, J=5.1, 9.0Hz), 4.85 (1H, t, J=9.0 Hz), 6.50 (1H, br s), 6.61 (1H, s), 6.66 (1H, d,J=8.1 Hz) 7.60 (1H, d, J=8.1 Hz)

EXAMPLE 186N-(3-(3-Hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(3-(4-isopropyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(500 mg, 1.18 mmol) obtained in Example 185 in dichloromethane (5 mL)was added dropwise at −70° C. under an argon atmosphere boron tribromide(1.0 M, dichloromethane solution, 2.36 mL, 2.36 mmol) and the resultingmixture was gradually warmed to room temperature.

Water was added to the reaction solution and the product was extractedwith ethyl acetate. The combined organic layers were washed with anaqueous saturated sodium hydrogen carbonate solution, dried overanhydrous sodium sulfate, and concentrated under reduced pressure toobtain 465 mg (yield: 96%) of the title compound. Melting point:220-221° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.17 (6H, d, J=6.9 Hz), 1.81 (3H, s),2.09 (3H, s), 2.12 (3H, s), 2.24 (2H, s), 3.15 (1H, septet, J=6.9 Hz),4.30-4.45 (2H, m), 4.74 (1H, t, J=9.0 Hz), 6.42 (1H, br s), 6.61 (1H, d,J=8.1 Hz), 6.87 (1H, br s), 7.03 (1H, d, J=8.1 Hz), 1H unidentified.

EXAMPLE 187N-(2-Hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(4-isopropyl-2-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 74, the title compound was synthesized in the samemanner as in Example 186. Yield: 98%. Melting point: 265-266° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.18 (6H, d, J=6.9 Hz), 1.90 (3H, s),2.15 (3H, s), 2.16 (3H, s), 2.27 (2H, s), 2.78 (1H, septet, J=6.9 Hz),4.42 (1H, dd, J=9.9, 13.8 Hz), 4.75-4.85 (2H, m), 5.26 (1H, br), 6.53(1H, br s), 6.62 (1H, s), 6.64 (1H, d, J=8.1 Hz), 6.76 (1H, d, J=8.1Hz).

EXAMPLE 188 Ethyl(5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-2-isopropylphenoxy)acetate

A mixed solution ofN-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(500 mg, 1.22 mmol) obtained in Example 186, ethyl bromoacetate (245 mg,1.47 mmol), potassium carbonate (253 mg, 1.83 mmol) and potassium iodide(10 mg) in acetone (10 mL) was heated for 16 hours under an argonatmosphere. Water was added to the reaction solution and the product wasextracted with ethyl acetate.

The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain 548 mg (yield: 91%) of thetitle compound. Melting point: 149-150° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.26 (3H, t,J=7.2 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.34(1H, septet, J=6.9 Hz), 4.21 (2H, q, J=7.2 Hz), 4.38 (1H, dd, J=4.8, 9.0Hz), 4.49 (1H, dd, J=4.8, 9.0 Hz), 4.55 (2H, s), 4.80 (1H, t, J=9.0 Hz),6.47 (1H, s), 6.50 (1H, br s), 6.72 (1H, d, J=7.8 Hz), 7.10 (1H, d,J=7.8 Hz).

EXAMPLE 189N-((3-(4-Isopropyl)-3-(2-oxopropoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 186 and chloroacetone, the title compound wasobtained in the same manner as in Example 188. Yield: 82%. Meltingpoint: 133-135° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 2.28 (3H, s), 3.34 (1H,septet, J=6.9 Hz), 4.39 (1H, dd, J=4.5, 9.0 Hz), 4.44 (2H, s), 4.50 (1H,dd, J=4.5, 9.0 Hz), 4.81 (1H, t, J=8.4 Hz), 6.39 (1H, s), 6.52 (1H, s),6.76 (1H, d, J=7.8 Hz), 7.14 (1H, d, J=7.8 Hz).

EXAMPLE 190Ethyl(2-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-5-isopropylphenoxy)acetate

UsingN-(2-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 187, the title compound was obtained in the samemanner as in Example 188. Yield: 90%. Melting point: 183-184° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.19 (6H, d, J=6.9 Hz), 1.29 (3H, t,J=7.2 Hz), 1.90 (3H, s), 2.16 (6H, s), 2.27 (2H, s), 2.82 (1H, septet,J=6.9 Hz), 4.26 (2H, q, J=7.2 Hz), 4.38 (1H, dd, J=3.9, 9.0 Hz), 4.68(2H, s), 4.83 (1H, t, J=9.0 Hz), 4.97 (1H, dd, J=3.9, 9.0 Hz), 6.53 (1H,br s), 6.58 (1H, s), 6.69 (2H, s).

EXAMPLE 191N-((4-Isopropyl-3-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl))-3,3-dimethylbutanamide

A mixed solution ofN-(3-(3-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(200 mg, 0.49 mmol) obtained in Example 186, 2-bromoethyl methyl ether(0.069 mL, 0.49 mmol), potassium carbonate (135 mg, 0.98 mmol) andpotassium iodide (10 mg) in acetonitrile (5 mL) was heated for 16 hoursunder an argon atmosphere. Water was added to the reaction solution andthe product was extracted with ethyl acetate. The organic layer waswashed with an aqueous saturated sodium hydrogen carbonate solution,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained residue was purified by basic silica gel columnchromatography (ethyl acetate hexane=2:3) to obtain 176 mg (yield: 77%)of the title compound. Melting point: 155-156° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.18 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.28 (1H, septet, J=6.9 Hz),3.44 (3H, s), 3.70-3.77 (2H, m), 4.02-4.06 (2H, m), 4.41 (1H, dd, J=4.8,8.7 Hz), 4.51 (1H, dd, J=4.8, 8.7 Hz), 4.82 (1H, t, J=8.7 Hz), 6.49 (1H,br s), 6.60 (1H, s), 6.69 (1H, d, J=7.8 Hz), 7.08 (1H, d, J=7.8 Hz).

EXAMPLE 192N-((4-Isopropyl-2-(2-methoxyethoxy)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl))-3,3-dimethylbutanamide

UsingN-(2-hydroxy-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 187, the title compound was synthesized in the samemanner as in Example 191. Yield: 59%. Melting point: 119-120° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.88 (3H, s),2.15 (6H, s), 2.27 (2H, s), 2.83 (1H, septet, J=6.9 Hz), 3.45 (3H, s),3.70-3.78 (2H, m), 4.14-4.18 (2H, m), 4.36 (1H, dd, J=4.2, 8.7 Hz), 4.83(1H, t, J=8.7 Hz), 4.91 (1H, dd, J=4.2, 8.7 Hz), 6.55 (1H, br s),6.65-6.75 (3H, m).

EXAMPLE 193N-(3-(3-(2-Hydroxyethoxy)-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of ethyl(5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-2-isopropylphenoxy)acetate(200 mg, 0.49 mmol) obtained in Example 188 in THF (5 mL) was added withice-cooling lithium borotetrahydride (43 mg, 2.00 mmol). The reactionsolution was warmed to room temperature and stirred for 60 hours. Thereaction solution was added to ice and water was added to the reactionsolution, and the product was extracted with ethyl acetate. The combinedorganic layers were washed with saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtain 157 mg(yield: 71%) of the title compound. Melting point: 155-156° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.18 (6H, d, J=6.9 Hz), 1.86 (3H, s),2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 3.25 (1H, septet, J=6.9 Hz),3.80-3.93 (2H, m), 4.00-4.04 (2H, m), 4.40 (1H, dd, J=4.8, 9.0 Hz),4.50-4.58 (1H, m), 4.82 (1H, t, J=9.0 Hz), 6.54 (1H, br s), 6.58 (1H,s), 6.73 (1H, d, J=8.1 Hz), 7.10 (1H, d, J=8.1 Hz), 1H unidentified.

EXAMPLE 194N-(3-(3-(3-Hydroxypropyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using ethyl3-(3-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)propanoateobtained in Example 180, the title compound was synthesized in the samemanner as in Example 193. Yield: 95%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.79 (3H, s), 1.79-1.92 (2H, m), 2.15(3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.57-2.70 (2H, m), 3.53 (2H, br),4.39 (1H, dd, J=5.1, 9.0 Hz), 4.57 (1H, dd, J=5.1, 9.0 Hz), 4.86 (1H, t,J=9.0 Hz), 6.56 (1H, br s), 6.91 (1H, br s), 6.99-7.05 (2H, m), 7.23(1H, t, J=7.8 Hz), 1H unidentified.

EXAMPLE 195N-(3-(4-(3-Hydroxypropyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using ethyl3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)propanoateobtained in Example 181, the title compound was synthesized in the samemanner as in Example 193. Yield: 77%. Melting point: 119-120° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.80-1.90 (5H, m), 2.14 (3H, s), 2.17(3H, s), 2.24 (2H, s), 2.65 (2H, t, J=7.8 Hz), 3.64 (2H, t, J=7.8 Hz),4.39 (1H, dd, J=4.8, 9.0 Hz), 4.52 (1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t,J=9.0 Hz), 6.56 (1H, br s), 7.04 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1Hz), 1H unidentified.

EXAMPLE 196N-(3-(4-(3-Hydroxy-1-methylpropyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using ethyl3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoateobtained in Example 182, the title compound was synthesized in the samemanner as in Example 193. Yield: 85%. Melting point: 145-147° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.24 (3H, d, J=7.2 Hz), 1.76-1.90 (2H,m), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.80-2.90(1H, m), 3.54 (2H, br), 4.41 (1H, dd, J=4.8, 9.0 Hz), 4.52 (1H, dd,J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 6.49 (1H, br s), 7.05 (2H, d,J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz), 1H unidentified.

EXAMPLE 197N-((4-Isopropyl-2-(2-hydroxyethoxy)-4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl))-3,3-dimethylbutanamide

Using ethyl2-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-5-isopropylphenoxy)acetateobtained in Example 190, the title compound was synthesized in the samemanner as in Example 193. Yield: 79%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.87 (3H, s),2.14 (3H, s), 2.18 (3H, s), 2.24 (2H, s), 2.85 (1H, septet, J=6.9 Hz),3.70-3.78 (2H, m), 3.93-4.00 (2H, m), 4.54 (1H, dd, J=4.5, 8.1 Hz), 4.66(1H, dd, J=4.5, 8.1 Hz), 4.80 (1H, t, J=8.1 Hz), 6.49 (1H, br s), 6.66(1H, s), 6.74 (1H, d, J=7.8 Hz), 7.01 (1H, d, J=7.8 Hz), 1Hunidentified.

EXAMPLE 1983-(4-(5-((3,3-Dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoicacid

Ethyl3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)butanoate(150 mg, 0.32 mmol) obtained in Example 182, 1 N aqueous sodiumhydroxide solution (2 mL) and THF (3 mL)-methanol (3 mL) were stirred atroom temperature for 16 hours. To the reaction solution was addedhydrochloric acid to make the solution acidic, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain 107 mg (yield: 74%) of thetitle compound. Melting point: 209-210° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.28 (3H, d, J=6.9 Hz), 1.81 (3H, s),2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.48-2.62 (2H, m), 3.15-3.26(1H, m), 4.38-4.42 (1H, m), 4.51 (1H, dd, J=4.2, 8.7 Hz), 4.81 (1H, t,J=8.7 Hz), 6.53 (1H, br s), 7.05 (2H, d, J=7.8 Hz), 7.10 (2H, d, J=7.8Hz), 1H unidentified.

EXAMPLE 199N-(3-(4-(1-Hydroxy-1-methylethyl)phenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-acetylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 176 and methylmagnesium bromide, the title compoundwas synthesized in the same manner as in Example 22. Yield: 42%. Meltingpoint: 132-134° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.55 (6H, s), 1.73 (1H, br s), 1.84 (3H,s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 4.41 (1H, dd, J=4.8, 9.0Hz), 4.54 (1H, dd, J=4.8, 9.0 Hz), 4.82 (1H, t, J=9.0 Hz), 6.53 (1H, brs), 7.10 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=8.1 Hz).

EXAMPLE 2004,4,4-Trifluoro-N-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

A mixed solution of3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine(200 mg, 0.68 mmol) obtained in Reference Example 30,4,4,4-trifluorobutanoic acid (116 mg, 0.82 mmol), N-hydroxybenzotriazole(111 mg, 0.82 mmol), (3-(dimethylamino)propyl)ethylcarbodiimidehydrochloride (196 mg, 1.02 mmol), N,N-dimethylaminopyridine (25 mg, 0.2mmol) in DMF (5 mL) was stirred at room temperature for 14 hours. Waterwas added to the reaction solution and the product was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure.

The obtained residue was purified by basic silica gel columnchromatography (ethyl acetate:hexane=3:7) to obtain 194 mg (yield: 68%)of the title compound. Melting point: 206-207° C. (THF-diisopropylether).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.81 (3H, s), 1.96-2.35 (8H,m), 2.38-2.62 (2H, m), 2.86 (1H, septet, J=6.9 Hz), 4.42 (1H, dd, J=4.8,9.0 Hz), 4.52 (1H, dd, J=4.8, 9.0 Hz), 4.86 (1H, t, J=9.0 Hz), 6.61 (1H,s), 7.00-7.05 (2H, m), 7.11-7.15 (2H, m).

EXAMPLE 201N′-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-N²,N²-dimethylglycineamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and N,N-dimethylglycine, the titlecompound was synthesized in the same manner as in Example 200. Yield:40%. Melting point: 95-96° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.84 (3H, s), 2.13 (3H, s),2.18 (3H, s), 2.40 (6H, s), 2.86 (1H, septet, J=6.9 Hz), 3.11 (2H, s),4.42 (1H, dd, J=4.5, 9.0 Hz), 4.53 (1H, dd, J=4.5, 9.0 Hz), 4.83 (1H, t,J=9.0 Hz), 7.05 (2H, d, J=8.1 Hz), 7.12 (2H, d, J=8.1 Hz), 8.45 (1H, brs).

EXAMPLE 202N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-2,2-dimethylpropanamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 30 and pivaloyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 76%.Melting point: 177-178° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.31 (9H, s), 1.80 (3H, s),2.09 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 4.38-4.43 (1H,m), 4.48-4.54 (1H, m), 4.81 (1H, t, J=8.8 Hz), 6.75 (1H, br), 7.03 (2H,d, J=8.1 Hz), 7.10 (2H, d, J=8.1 Hz).

EXAMPLE 203N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide

UsingN-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamideobtained in Example 58 and acetyl chloride, the title compound wasobtained in the same manner as in Example 38. Yield: 48%. Melting point:177-179° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.24 (6H, m), 1.88 and 1.94 (3H), 2.25 and 2.28 (3H),2.59 and 2.61 (3H), 2.81-2.85 (1H, m), 4.43-4.58 (2H, m), 4.88-4.98 (H,m), 6.63 and 6.66 (1H), 7.01-7.05 (2H, m), 7.13-7.18 (2H, m), 7.92 and8.39 (1H).

EXAMPLE 204N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(tert-butyl)urea

7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine(711 mg, 2.2 mmol) obtained in Reference Example 344 was dissolved inN,N-dimethylacetamide (10 mL), to the reaction solution was addedtert-butyl isocyanate (0.30 mL, 2.64 mmol) at room temperature, and thenthe mixture was heated at 60° C. The mixture was heated for 16 hours, tothe mixture was further added tert-butyl isocyanate (0.30 mL, 2.64mmol), and then the resulting mixture was stirred at 60° C. for 24hours. The reaction solution was cooled to room temperature and pouredinto water, and the product was extracted with ethyl acetate. Theextract was washed with saturated brine, dried over sodium sulfate, andthen concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:1)to obtain 70 mg (yield: 12%) of the title compound. Melting point:207-208° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20-1.18 (15H, m), 1.92 (3H, s), 2.29 (3H, s), 2.61(3H, s), 2.88 (1H, septet, J=7.0 Hz), 3.98 (1H, br), 4.50-4.59 (2H, m),4.90-4.98 (1H, m), 5.28 (1H, br), 7.00 (2H, d, J=8.2 Hz), 7.15 (2H, d,J=8.2 Hz).

EXAMPLE 205N-(Cyclohexyl)-N′-(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using 2,2,2,-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 138 and cyclohexylamine, the title compound wasobtained in the same manner as in Example 143.

Yield: 92%. Melting point: 210-211° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.78-1.17 (3H, m), 1.21 (6H, d, J=6.9 Hz), 1.21-1.38(2H, m), 1.50-1.67 (3H, m), 1.78-1.88 (4H, m), 2.14-2.20 (7H, m), 2.86(1H, septet, J=6.9 Hz), 3.61 (1H, br), 3.98 (1H, br), 4.42-4.47 (1H, m),4.51-4.57 (1H, m), 4.86 (1H, t, J=9.0 Hz), 5.42 (1H, s), 6.99 (2H, d,J=8.2 Hz), 7.12 (2H, d, J=8.2 Hz).

EXAMPLE 206 2,2,2-Trichloroethyl(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 344 and 2,2,2-trichloroethylchloroformate, the title compound was obtained in the same manner as inExample 138.

Yield: 91%. Melting point: 186-189° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.93 (3H, s), 2.28 (3H, s),2.60 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 4.47-4.59 (2H, m), 4.75-4.96(3H, m), 6.16 (1H, s), 7.03 (2H, d, J=8.0 Hz), 7.15 (2H, d, J=8.0 Hz).

EXAMPLE 207N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(3-hydroxypropyl)urea

Using 2,2,2-trichloroethyl(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 206 and 3-hydroxypropylamine, the title compound wasobtained in the same as manner as in Example 143. Yield: 59%.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.57 (2H, br), 1.93 (3H, s),2.28 (3H, s), 2.61 (3H, s), 2.85 (1H, septet, J=6.9 Hz), 3.33 (2H, br),3.58 (2H, br), 4.50-4.59 (3H, m), 4.92 (1H, t, J=10.3 Hz), 5.52 (1H,br), 7.02 (2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz).

EXAMPLE 208N-(tert-Butyl)-N′-(3-(4-isopropylphenyl)-7-(1-hydroxyethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

To a solution ofN-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(tert-butyl)urea(718 mg, 1.7 mmol) obtained in Example 204 in methanol (10 mL) was addedsodium borohydride (64.3 mg, 1.7 mmol) at 0° C., and the resultingmixture was stirred for 3 hours. The reaction solution was diluted withwater and the product was extracted with ethyl acetate. The extract waswashed with saturated brine, dried over sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain115 mg (yield: 16%) of the title compound having high polarity of twoisomers. Melting point: 212-214° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20-1.27 (15H, m), 1.52-1.58 (3H, m), 1.89 (3H, s),2.23 (3H, s), 2.87 (1H, septet, J=7.0 Hz), 3.57 (1H, br), 4.03 (1H, br),4.47-4.57 (2H, m), 4.88-4.97 (1H, m), 5.01-5.08 (1H, m), 5.26 (1H, br),6.98 (2H, d, J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz).

EXAMPLE 209N-(tert-Butyl)-N′-(3-(4-isopropylphenyl)-7-ethyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

UsingN-(tert-butyl)-N′-(3-(4-isopropylphenyl)-7-(1-hydroxyethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)ureaobtained in Example 208, the title compound was obtained in the samemanner as in Example 23. Yield: 53%. Melting point: 207-209° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12-1.30 (18H, m), 1.87 (3H, s), 2.22 (3H, s),2.61-2.72 (2H, m), 2.86 (1H, septet, J=6.9 Hz), 4.00 (1H, br), 4.42-4.46(1H, m), 4.50-4.56 (1H, m), 4.86 (1H, t, J=9.0 Hz), 5.28 (1H, br), 6.98(2H, d, J=8.1 Hz), 7.11 (2H, d, J=8.1 Hz).

EXAMPLE 210N-(7-Acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N′-(2-hydroxyethyl)urea

Using 2,2,2-trichloroethyl(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 206 and 2-hydroxyethylamine, the title compound wasobtained in the same manner as in Example 143. Yield: 66%.

¹H-NMR (CDCl₃) δ: 1.23 (6H, d, J=6.9 Hz), 1.94 (3H, s), 2.29 (3H, s),2.60 (3H, s), 2.80-2.97 (2H, m), 3.32 (2H, br), 3.63 (2H, br), 4.49-4.57(2H, m), 4.63 (1H, br), 4.92 (1H, t, J=10.1 Hz), 5.63 (1H, br), 7.01(2H, d, J=8.1 Hz), 7.15 (2H, d, J=8.1 Hz).

EXAMPLE 211N-(3-(4-Isopropylphenyl)-4,6-dimethyl-7-(3-(1-pyrrolidinyl)phenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (3-(1-pyrrolidinyl)phenyl)boronic acid, thetitle compound was obtained in the same manner as in Example 107. Yield:17%. Melting point: 206-207° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.24 (6H, d, J=6.9 Hz), 1.92 (3H, s),1.95-2.04 (4H, m), 2.10 (3H, s), 2.26 (2H, d, J=1.4 Hz), 2.87 (1H,septet, J=6.9 Hz), 3.23-3.33 (4H, m), 4.36 (1H, dd, J=5.2, 8.7 Hz), 4.57(1H, dd, J=5.2, 9.2 Hz), 4.79 (1H, dd, J=8.7, 9.2 Hz), 6.48-6.65 (4H,m), 7.11 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.7 Hz), 7.27

(1H, t, J=7.7 Hz).

EXAMPLE 212N-(7-(4-(Dimethylamino)phenyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (4-(dimethylamino)phenyl)boronic acid, thetitle compound was obtained in the same manner as in Example 107. Yield:17%. Melting point: 180-181° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.23 (6H, d, J=7.1 Hz), 1.92 (3H, s),2.11 (3H, s), 2.27 (2H, d, J=1.4 Hz), 2.87 (1H, septet, J=7.0 Hz), 2.98(6H, s), 4.38 (1H, dd, J=4.9, 8.5 Hz), 4.55 (1H, dd, J=4.9, 9.4 Hz),4.79 (1H, dd, J=8.5, 9.4 Hz), 6.50 (1H, s), 6.80 (2H, d, J=7.7 Hz), 7.10(2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.6 Hz), 7.21 (2H, d, J=7.7 Hz).

EXAMPLE 213N-(7-(6-(Dimethylamino)pyridin-3-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 35 and (6-(dimethylamino)pyridin-3-yl)boronic acid,the title compound was obtained in the same manner as in Example 107.Yield: 26%. Melting point: 217-220° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.92 (3H, s),2.12 (3H, s), 2.26 (2H, d, J=1.4 Hz), 2.86 (1H, septet, J=6.9 Hz), 3.12(6H, s), 4.38 (1H, dd, J=4.9, 8.8 Hz), 4.56 (1H, dd, J=4.9, 9.4 Hz),4.79 (1H, dd, J=8.8, 9.4 Hz), 6.53 (1H, s), 6.59 (1H, dd, J=0.8, 8.8Hz), 7.09 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 7.47 (1H, dd,J=2.3, 8.8 Hz), 8.15 (1H, dd, J=0.8, 2.3 Hz).

EXAMPLE 214N-(7-(4-Isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using7-(4-isopropylbenzyl)-3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 292, the title compound was synthesized inthe same manner as in Example 1. Yield: 66%. Melting point: 185-186° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.19 (6H, d, J=6.9 Hz), 1.27 (3H, d,J=6.9 Hz), 2.07 (3H, s), 2.27 (2H, s), 2.30 (3H, s), 2.80-2.90 (1H,septet, J=6.9 Hz), 3.40-3.55 (1H, m), 3.93 (2H, m), 4.20 (1H, dd, J=3.3,8.7 Hz), 4.55 (1H, t, J=8.7 Hz), 6.51 (1H, br s), 7.07 (4H, s).

EXAMPLE 215N-(3-Ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-ethyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 293, the title compound was synthesized inthe same manner as in Example 1. Yield: 53%. Melting point: 156-157° C.(hexane).

¹H-NMR (CDCl₃) δ: 0.92 (3H, t, J=7.5 Hz), 1.13 (9H, s), 1.20 (6H, d,J=6.9 Hz), 1.50-1.61 (2H, m), 2.07 (3H, s), 2.16 (3H, s), 2.27 (2H, s),2.83 (1H, septet, J=6.9 Hz), 3.24-3.33 (1H, m), 3.92 (2H, s), 4.37 (1H,dd, J=3.0, 9.0 Hz), 4.48 (1H, t, J=9.0 Hz), 6.50 (1H, br s), 7.06 (4H,s).

EXAMPLE 216N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using7-(4-isopropylbenzyl)-4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 294, the title compound was synthesized inthe same manner as in Example 1. Yield: 57%. Melting point: 144-145° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.93 (3H, t, J=7.2 Hz), 1.13 (9H, s), 1.19 (6H, d,J=6.9 Hz), 1.30-1.43 (2H, m), 1.50-1.63 (2H, m), 2.06 (3H, s), 2.16 (3H,s), 2.26 (2H, s), 2.83 (1H, septet, J=6.9 Hz), 3.30-3.41 (1H, m), 3.92(2H, s), 4.35 (1H, dd, J=3.3, 9.0 Hz), 4.46 (1H, t, J=8.7 Hz), 6.48 (1H,br s), 7.05 (4H, s).

EXAMPLE 217N-(3-Isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-isopropyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 295, the title compound was synthesized inthe same manner as in Example 1. Yield: 88%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 0.73 (3H, d, J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.19(6H, d, J=6.9 Hz), 2.06 (3H, s), 2.16 (3H, s), 2.26 (2H, s), 2.82 (1H,septet, J=6.9 Hz), 3.31-3.36 (1H, m), 3.85 (1H, d, J=15.6 Hz), 3.96 (1H,d, J=15.6 Hz), 4.35 (1H, t, J=9.0 Hz), 4.49 (1H, dd, J=2.7, 9.0 Hz),6.48 (1H, br s), 7.04 (4H, s)

EXAMPLE 218N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 298 and n-butanoyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 81%.Melting point: 168-169° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.03 (3H, t, J=7.5 Hz), 1.20 (6H, d, J=6.9 Hz),1.72-1.89 (2H, m), 2.06 (3H, s), 2.10 (3H, s), 2.36 (2H, t, J=7.5 Hz),2.84 (1H, septet, J=6.9 Hz), 3.15 (2H, t, J=8.7 Hz), 3.92 (2H, s), 4.55(2H, t, J=8.7 Hz), 6.55 (1H, br s), 7.06 (4H, s).

EXAMPLE 219N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)propanamide

Using7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 298 and n-propanoyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 78%.Melting point: 177-178° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.29 (3H, t, J=7.5 Hz), 2.06(3H, s), 2.10 (3H, s), 2.41 (2H, q, J=7.5 Hz), 2.78-2.88 (1H, septet,J=6.9 Hz), 3.15 (2H, t, J=8.7 Hz), 3.92 (2H, s), 4.56 (2H, t, J=8.7 Hz),6.56 (1H, br s), 6.99-7.10 (4H, m).

EXAMPLE 220N-(7-(1-(4-Isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)pentanamide

Using7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 298 and n-pentanoyl chloride, the titlecompound was synthesized in the same manner as in Example 1. Yield: 82%.Melting point: 172-173° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.96 (3H, t, J=7.5 Hz), 1.20 (6H, d, J=6.9 Hz),1.33-1.53 (2H, m), 1.69-1.79 (2H, m), 2.06 (3H, s), 2.10 (3H, s), 2.39(2H, t, J=7.5 Hz), 2.78-2.88 (1H, septet, J=6.9 Hz), 3.18 (2H, t, J=8.4Hz), 3.92 (2H, s), 4.56 (2H, t, J=8.4 Hz), 6.54 (1H, br s), 7.01-7.13(4H, m).

EXAMPLE 221 tert-Butyl(4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using 4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained inReference Example 297, the title compound was synthesized in the samemanner as in Reference Example 59. Yield: 96%. Melting point: 121-122°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.50 (9H, br), 2.14 (3H, s), 2.20 (3H, s), 3.09 (2H,t, J=8.7 Hz), 4.54 (2H, t, J=8.7 Hz), 5.73 (1H, br s), 6.50 (1H, s).

EXAMPLE 222 tert-Butyl(7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl (4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 221, the title compound was synthesized in the samemanner as in Reference Example 66. Yield: 93%. Melting point: 176-177°C. (methanol).

¹H-NMR (CDCl₃) δ: 1.50 (9H, br), 2.13 (3H, s), 2.32 (3H, s), 3.23 (2H,t, J=8.4 Hz), 4.66 (2H, t, J=8.4 Hz), 5.83 (1H, br s).

EXAMPLE 223 tert-Butyl(7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

To a mixed solution of tert-butyl(7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtainedin Example 222 (500 mg, 1.46 mmol) and cerous chloride (360 mg, 3.21mmol) in THF (8 mL) was added dropwise at −78° C. under an argonatmosphere n-butyllithium (1.6 M hexane solution, 2.0 mL, 3.21 mmol).The mixture was stirred at the same temperature for 30 minutes, and thento the reaction solution was added dropwise a solution of4-isopropylacetophenone (261 mg, 1.61 mmol) in THF (4 mL) and theresulting mixture was stirred for 30 minutes and elevated to roomtemperature. Water was added to the reaction solution and the productwas extracted with ethyl acetate. The combined organic layers werewashed with saturated brine, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethylacetate:hexane=2:3) to obtain 118 mg (yield: 19%) the title compound.Melting point: 185-186° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.22 (6H, d, J=6.9 Hz), 1.46 (9H, br), 1.56 (3H, brs), 1.97 (3H, s), 2.15 (3H, s), 2.87 (1H, septet, J=6.9 Hz), 3.12 (2H,t, J=8.7 Hz), 4.58 (2H, t, J=8.7 Hz), 4.81 (1H, br s), 5.66 (1H, br s),7.11 (2H, d, J=8.1 Hz), 7.28 (2H, d, J=8.1 Hz).

EXAMPLE 224N-(7-(1-(4-Isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a mixed solution of tert-butyl7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate(120 mg, 0.28 mmol) obtained in Example 223 in trifluoroacetic acid (1.5mL) was added dropwise triethylsilane (66 mg, 0.56 mmol), and themixture was stirred at room temperature for 1 hour. Water was added tothe reaction solution and the product was extracted with ethyl acetate.The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure to obtainN-(7-(1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)amine.To a solution of the compound and triethylamine (0.047 mL, 0.34 mmol) inTHF (3 mL) was added dropwise with ice-cooling n-butanoyl chloride(0.034 mL, 0.34 mmol). Water was added to the reaction solution and theproduct was extracted with ethyl acetate. The combined organic layerswas washed with saturated brine, dried over anhydrous sodium sulfate,filtered, and then concentrated under reduced pressure to obtain 62 mg(yield: 58%) of the title compound. Melting point: 152-153° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.03 (3H, t, J=7.5 Hz), 1.21 (6H, d, J=6.9 Hz), 1.66(3H, d, J=7.5 Hz), 1.71-1.89 (2H, m), 2.04 (3H, s), 2.09 (3H, s), 2.36(2H, t, J=7.5 Hz), 2.84 (1H, septet, J=6.9 Hz), 3.09 (2H, t, J=8.7 Hz),4.43-4.60 (3H, m), 6.52 (1H, br s), 7.07 (2H, d, J=8.1 Hz), 7.16 (2H, d,J=8.1 Hz).

EXAMPLE 225N-(7-(1-(4-Isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using tert-butyl(7-(1-hydroxy-1-(4-isopropylphenyl)ethyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 223 and tert-butylacetyl chloride, the titlecompound was synthesized in the same manner as in Example 224. Yield:61%. Melting point: 189-190° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.66 (3H, d,J=7.2 Hz), 2.05 (3H, s), 2.11 (3H, s), 2.26 (2H, s), 2.84 (1H, septet,J=6.9 Hz), 3.09 (2H, t, J=8.7 Hz), 4.40-4.55 (3H, m), 6.47 (1H, br s),7.07 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz).

EXAMPLE 226N-(7-(1-(4-Isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(7-(1-(4-isopropylphenyl)vinyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)amineobtained in Reference Example 334, the title compound was synthesized inthe same manner as in Example 1. Yield: 51%. Melting point: 188-189° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.99 (3H, s),2.18 (3H, s), 2.28 (2H, s), 2.86 (1H, septet, J=6.9 Hz), 3.15 (2H, t,J=8.7 Hz), 4.51 (2H, t, J=8.7 Hz), 5.14 (1H, s), 5.92 (1H, s), 6.53 (1H,br s), 7.10 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.1 Hz).

EXAMPLE 227N-(tert-Butyl)-N′-(7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 298 and tert-butylamine, the titlecompound was synthesized in the same manner as in Example 47. Yield:83%. Melting point: 197-198° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 1.24 (9H, s), 2.11 (3H, s),2.16 (3H, s), 2.78-2.88 (1H, septet, J=6.9 Hz), 3.17 (2H, t, J=8.4 Hz),3.94 (2H, s), 4.04 (1H, br s), 4.60 (2H, t, J=8.4 Hz), 5.30 (1H, br s),7.02 (2H, d, J=8.1 Hz), 7.07 (2H, d, J=8.1 Hz).

EXAMPLE 228N-(2-Hydroxyethyl)-N′-(7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea

Using7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 298 and 2-hydroxyethylamine, the titlecompound was synthesized in the same manner as in Example 47. Yield:80%. Melting point: 176-177° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.20 (6H, d, J=6.9 Hz), 2.14 (3H, s), 2.17 (3H, s),2.78-2.88 (1H, septet, J=6.9 Hz), 3.06 (1H, t, J=4.5 Hz), 3.16 (2H, t,J=8.4 Hz), 3.28-3.34 (2H, m), 3.60-3.66 (2H, m), 3.94 (2H, br s), 4.60(2H, t, J=8.4 Hz), 4.65 (1H, br s), 5.64 (1H, s), 7.07 (4H, s).

EXAMPLE 229N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-benzyl-N-(3-bromo-4-chloroethoxy-5-(4-isopropylbenzyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide(486 mg, 0.81 mmol) obtained in Reference Example 338 in THF (8 mL) wasadded dropwise at −50° C. under an argon atmosphere n-butyllithium (1.6M hexane solution, 0.56 mL, 0.89 mmol), and the mixture was stirred for30 minutes. The reaction solution was warmed to room temperature, waterwas added to the reaction solution, and the product was extracted withethyl acetate. The combined organic layers were washed with saturatedbrine, dried over anhydrous sodium sulfate, filtered, and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (ethyl acetate:hexane=1:4) to obtain 186 mg(yield: 47%) ofN-benzyl-N-(7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide.A mixed solution of the compound (186 mg, 0.38 mmol) and 10% palladiumon carbon (water content: 50%, 19 mg) in acetic acid (2 mL) was stirredat 85° C. for 14 hours under a hydrogen atmosphere. The reactionsolution was filtered through celite, and water was added to filtrateand the product was extracted with ethyl acetate. The combined organiclayers were washed with an aqueous saturated sodium hydrogen carbonatesolution, dried over anhydrous sodium sulfate, filtered, and thenconcentrated under reduced pressure to obtain 60 mg (yield: 40%) of thetitle compound. Melting point: 201-202° C. (ethyl acetate-hexane).¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.20 (6H, d, J=6.9 Hz), 2.08 (3H, s),2.13 (3H, s), 2.27 (2H, s), 2.83 (1H, septet, J=6.9 Hz), 3.15 (2H, t,J=5.7 Hz), 3.92 (2H, s), 4.56 (2H, t, J=5.7 Hz), 6.51 (1H, br s), 7.07(4H, s).

EXAMPLE 230N-(3-Hydroxymethyl-7-(4-isopropylbenzyl)-4,6-dimethylphenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(4-(allyloxy)-3-bromo-5-(4-isopropylbenzyl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide(674 mg, 1.39 mmol) obtained in Reference Example 340 in dichloromethane(7 mL) was added with ice-cooling m-chloroperbenzoic acid (239 mg, 1.39mmol) and the mixture was stirred for 30 minutes. The reaction solutionwas added to an aqueous saturated sodium hydrogen carbonate solution andthe product was extracted with ethyl acetate. The combined organiclayers were washed with a 10% aqueous sodium sulfite solution, driedover anhydrous sodium sulfate, filtered, and then concentrated underreduced pressure to obtainN-(3-bromo-5-(4-isopropylbenzyl)-2,6-dimethylphenyl-4-(oxiran-2-ylmethoxy)-3,3-dimethylbutanamide.To a solution of the compound in THF (5 mL) was added dropwise at −78°C. under an argon atmosphere n-butyllithium (1.6 M hexane solution, 0.83mL, 1.33 mmol), and the mixture was stirred for 30 minutes. The reactionsolution was warmed to room temperature and added to water, and theproduct was extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate, filtered, and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) to obtain 162 mg (yield: 28%)of the title compound. Melting point: 136-137° C. (THF-hexane).

¹H-NMR (CDCl₃) δ: 1.07 (9H, s), 1.19 (6H, d, J=6.9 Hz), 2.07 (3H, s),2.17 (3H, s), 2.26 (2H, s), 2.82 (1H, septet, J=6.9 Hz), 3.50-3.76 (3H,m), 3.92 (2H, s), 4.48 (1H, t, J=9.0 Hz), 4.61 (1H, dd, J=2.4, 9.0 Hz),6.52 (1H, br s), 7.05 (4H, s), 1H unidentified.

EXAMPLE 231N-(4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained inReference Example 358, the title compound was synthesized in the samemanner as in Example 1.

Yield: 97%. Melting point: 158-159° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.85 (3H, s), 2.22 (3H, s), 2.24 (2H,s), 4.41 (1H, dd, J=8.7, 4.8 Hz), 4.53 (1H, dd, J=9.3, 4.8 Hz), 4.85(1H, t, J=9.3 Hz), 6.45 (1H, br s), 6.63 (1H, s), 7.09-7.30 (5H, m).

EXAMPLE 232 N-(7-Formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 231, the title compound was synthesized in the samemanner as in Example 20. Yield: 74%. Oily matter.

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.91 (3H, s), 2.27 (2H, s), 2.53 (3H,s), 4.53-4.62 (2H, m), 5.00 (1H, dd, J=10.2 Hz), 6.45 (1H, br s), 7.13(2H, d, J=7.8 Hz), 7.20-7.35 (3H, m), 10.5 (1H, s).

EXAMPLE 233N-(7-(4-Isopropylbenzyl)-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount ofiodine was added dropwise under an argon atmosphere a solution of4-isopropyl-1-bromobenzene (978 mg, 4.91 mmol) in THF (10 mL) and themixture was stirred at room temperature for 20 minutes. To the reactionsolution was added dropwise a solution ofN-(7-formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(200 mg, 0.547 mmol) obtained in Example 232 in THF (5 mL) and themixture was stirred at room temperature for 1 hour. The reactionsolution was added to ice and the product was extracted with ethylacetate. The organic layer was washed with 1 N hydrochloric acid andwater, dried over anhydrous sodium sulfate, and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:2) to obtainN-(7-(hydroxy(4-isopropylphenyl)methyl)-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide.To a mixture of the compound and trifluoroacetic acid (5 mL) was addedwith ice-cooling triethylsilane (0.161 mL, 1.01 mmol), and the mixturewas stirred at room temperature for 30 minutes. After the reactionsolution was concentrated under reduced pressure, to the residue wasadded an aqueous saturated sodium bicarbonate solution and the aqueouslayer was made alkaline, and the mixture was extracted with ethylacetate.

The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) and crystallized from hexane to obtain 70 mg(yield: 28%) of the title compound. Melting point: 137-141° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.85 (3H, s),2.11 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J=6.9 Hz), 4.00 (2H, s),4.42 (1H, dd, J=8.7, 4.8 Hz), 4.58 (1H, dd, J=13.8, 4.8 Hz), 4.85 (1H,d, J=6.6 Hz), 6.45 (1H, br s), 7.05-7.35 (9H, m).

EXAMPLE 234N-(3-Hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide(1.0 g, 3.15 mmol) obtained in Reference Example 63 in methanol (100 mL)was added sodium borohydride (238 mg, 6.30 mmol) at room temperature,and the mixture was stirred for 1 hour. The reaction solution wasconcentrated under reduced pressure, and the residue was extracted withethyl acetate. The organic layer was washed with water, dried overanhydrous sodium sulfate, and then concentrated under reduced pressure.The obtained residue was crystallized from ethyl acetate to obtain 950mg (yield: 94%) of the title compound. Melting point: 204-206° C.

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.29 (3H, s), 1.49 (3H, s), 2.09 (3H,s), 2.11 (3H, s), 2.23 (3H, s), 2.30 (2H, s), 4.70 (1H, d, J=9.2 Hz),6.61 (1H, br s), 1H unidentified.

EXAMPLE 235N-(3-Hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65, the title compound was synthesized inthe same manner as in Example 234. Yield: 92%. Melting point: 184-185°C. (THF-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.32 (3H, s), 1.48 (3H, s), 1.81 (1H,brs), 2.13 (6H, s), 2.25 (2H, s), 4.73 (1H, brs), 6.79 (1H, brs), 7.34(1H, s).

EXAMPLE 236 tert-Butyl(7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(7-bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 66, the title compound was synthesized inthe same manner as in Example 234. Yield: 98%. Melting point: 187-188°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.28-1.71 (15H, m), 1.70 (1H, brs), 2.26 (3H, s), 2.34(3H, s), 4.80 (1H, d, J=9.0 Hz), 5.84 (1H, brs).

EXAMPLE 237 tert-Butyl(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

A mixture ofN-benzyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine (4.1 g,14.6 mmol) obtained in Reference Example 98, 10% palladium on carbon(water content: 50%, 400 mg) and ammonium formate (1.84 g, 29.2 mmol) inmethanol (70 mL) was refluxed with heating for 2 hours. The catalyst wasfiltered off, and the filtrate was distilled off under reduced pressure.Water and ethyl acetate were added to the residue. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the obtained residue was crystallized from ethyl acetate-hexane toobtain 2.60 g of 2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-ylamine.A solution of the compound (2.60 g, 13.5 mmol) and di-tert-butyldicarbonate (6.20 mL, 27.0 mmol) in THF (50 mL) was refluxed withheating for 16 hours. Water was added to the reaction solution. Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic layers were washed with water anddried over anhydrous sodium sulfate, and the solvent was distilled offunder reduced pressure. The obtained residue was crystallized fromhexane-ethyl acetate to obtain 2.57 g (yield: 60%) of the titlecompound. Melting point: 121-123° C.

¹H-NMR (CDCl₃) δ: 1.45 (6H, s), 1.50 (9H, s), 2.11 (3H, s), 2.19 (3H,s), 2.90 (2H, s), 5.72 (1H, br s), 6.44 (1H, s).

EXAMPLE 238 tert-Butyl(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using (2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamic acidobtained in Example 237, the title compound was synthesized in the samemanner as in Reference Example 18. Yield: 54%. Melting point: 115-117°C.

¹H-NMR (CDCl₃) δ: 1.38-1.59 (15H, m), 2.08 (3H, s), 2.31 (3H, s), 3.01(2H, s), 5.81 (1H, br s).

EXAMPLE 239N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide(303 mg, 1 mmol) obtained in Reference Example 65 in THF (10 mL) wasadded dropwise at 0° C. under an argon atmosphere a solution of3-tolylmagnesium bromide (1.0 M, 10 mL, 10 mmol) in THF, and the mixturewas warmed to room temperature. The mixture was stirred for 1 hour, andthe reaction solution was added to ice and the product was extractedwith ethyl acetate. The organic layer was washed with water andsaturated brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure. The obtained residue wasrecrystallized from ethyl acetate-hexane to obtain 265 mg (yield: 67%)of the title compound. Melting point: 113-114° C.

¹H-NMR (CDCl₃) δ: 0.86 (3H, s), 1.10 (9H, s), 1.59 (3H, s), 2.18-2.22(8H, m), 2.36 (3H, s), 2.40 (1H, brs), 6.80 (1H, brs), 7.10-7.20 (2H,m), 7.22-7.26 (2H, m), 7.35 (1H, s).

EXAMPLE 240N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution of 2-chloroethylbenzene (648 mg, 4.6 mmol) in THF (5 mL) wasadded dropwise under an argon atmosphere to a mixture of magnesium (112mg, 4.6 mmol) and a catalytic amount of iodine, and the mixture wasstirred for 30 minutes. To the reaction solution was added dropwise asolution of3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide(300 mg, 0.98 mmol) obtained in Reference Example 65 in THF (3 mL), andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was added to ice and the product was extracted with ethylacetate. The extract was washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(ethyl acetate:hexane=2:3) and recrystallized from ethyl acetate-hexaneto obtain 201 mg (yield: 51%) of the title compound. Melting point:99-100° C.

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.37 (3H, s), 1.54 (3H, s), 1.99-2.30(1H, m), 2.80 (1H, dt, J=12.9, 4.8 Hz), 2.97 (1H, dt, J=12.9, 4.8 Hz),6.77 (1H, brs), 7.15-7.31 (6H, m).

EXAMPLE 241N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-(trifluoromethoxy)phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of 1-bromo-2-(trifluoromethoxy)benzene (827 mg, 3.43 mmol)in THF (8 mL) was added dropwise at −78° C. under an argon atmospheren-butyllithium (1.59 M hexane solution, 1.85 mL, 2.94 mmol), and themixture was stirred for 30 minutes. To the reaction solution was addeddropwise at −78° C. a solution of3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide(300 mg, 0.98 mmol) obtained in Reference Example 65 in THF (3 mL), andthe mixture was stirred for 30 minutes. The reaction solution was warmedto room temperature and stirred for 1 hour, and water was added to thereaction solution and the product was extracted with ethyl acetate.

The organic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate:hexane=2:3), and then recrystallized from ethyl acetate-hexaneto obtain 267 mg (yield: 59%) of the title compound. Melting point:160-161° C.

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.11 (9H, s), 1.62 (3H, s), 2.18 (6H,s), 2.22 (2H, s), 3.00 (1H, brs), 6.79 (1H, brs), 7.15-7.36 (5H, m).

EXAMPLE 242N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 2-tolylmagnesium bromide, the titlecompound was synthesized in the same manner as in Example 239.

Yield: 43%. Melting point: 111-112° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.10 (9H, s), 1.68 (3H, s), 2.17-2.26(9H, m), 2.64 (3H, s), 6.82 (1H, brs), 6.90-7.26 (5H, m).

EXAMPLE 243N-(3-Hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and phenyllithium, the title compoundwas synthesized in the same manner as in Example 241. Yield: 58%.Melting point: 109-111° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.85 (3H, s), 1.10 (9H, s), 1.62 (3H, s), 2.18-2.22(8H, m), 2.37 (1H, brs), 6.79 (1H, brs), 7.12 (1H, s), 7.27-7.38 (3H,m), 7.47-7.50 (2H, m).

EXAMPLE 244N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 2-bromonaphthalene, the titlecompound was synthesized in the same manner as in Example 240. Yield:65%. Melting point: 142-144° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.89 (3H, s), 1.09 (9H, s), 1.65 (3H, s), 2.20-2.24(8H, m), 2.46 (1H, brs), 6.82 (1H, brs), 7.16 (1H, s), 7.46-7.51 (2H,m), 7.60 (1H, d, J=8.8 Hz), 7.80-7.86 (3H, m), 7.99 (1H, s).

EXAMPLE 245N-(3-Hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 1-bromo-3-isopropylbenzene, thetitle compound was synthesized in the same manner as in Example 240.Yield: 76%. Melting point: 136-137° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.84 (3H, s), 1.10 (9H, s), 1.22 (6H, d, J=6.9 Hz),1.60 (3H, s), 2.14-2.22 (9H, m), 2.90 (1H, septet, J=6.9 Hz), 6.77 (1H,brs), 7.14-7.18 (2H, m), 7.23-7.28 (2H, m), 7.39 (1H, s).

EXAMPLE 246N-(3-Hydroxy-3-(2-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 2-methoxyphenylmagnesium bromide,the title compound was synthesized in the same manner as in Example 239.Yield: 58%. Melting point: 168-169° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.92 (3H, s), 1.10 (9H, s), 1.66 (3H, s), 2.15-2.21(8H, m), 3.94 (3H, s), 5.17 (1H, brs), 6.82 (1H, brs), 6.89-6.97 (2H,m), 7.09 (1H, s), 7.12 (1H, d, J=8.1 Hz), 7.28 (1H, d, J=8.1 Hz).

EXAMPLE 247N-(3-Hydroxy-3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 1-bromo-4-isopropylbenzene, thetitle compound was synthesized in the same manner as in Example 240.Yield: 42%. Melting point: 119-121° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.84 (3H, s), 1.11 (9H, s), 1.26 (6H, d, J=6.9 Hz),1.60 (3H, s), 2.18-2.22 (8H, m), 2.29 (1H, s), 2.86 (1H, septet, J=6.9Hz), 6.80 (1H, br s), 7.15 (1H, s), 7.21 (2H, d, J=8.0 Hz), 7.41 (2H, d,J=8.0 Hz).

EXAMPLE 248N-(3-Hydroxy-2,2,6,7-tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 2-bromothiophene, the titlecompound of oily matter was obtained in the same manner as in Example240. Yield: 86%.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.12 (9H, s), 1.64 (3H, s), 2.18 (3H,s), 2.19 (3H, s), 2.23 (2H, s), 2.63 (1H, brs), 6.81 (1H, brs),6.94-7.01 (2H, m), 7.29-7.32 (2H, m).

EXAMPLE 249N-(3-Benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and benzylmagnesium chloride, the titlecompound was synthesized in the same manner as in Reference Example 239.Yield: 88%. Melting point: 212-213° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.08 (9H, s), 1.31 (3H, s), 1.43 (3H, s), 1.75 (1H,s), 2.09-2.17 (8H, m), 3.02 (1H, d, J=13.6 Hz), 3.16 (1H, d, J=13.6 Hz),6.56 (1H, s), 6.66 (1H, brs), 7.20-7.38 (5H, m).

EXAMPLE 250N-(3-Hydroxy-3-(4-isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 4-isopropylbenzyl chloride, thetitle compound was synthesized in the same manner as in Example 240.Yield: 94%. Melting point: 177-178° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.25 (6H, d, J=6.9 Hz), 1.33 (3H, s),1.43 (3H, s), 2.04 (1H, s), 2.11 (3H, s), 2.14 (3H, s), 2.19 (2H, m),2.90 (1H, septet, J=6.9 Hz), 3.00 (1H, d, J=13.6 Hz), 3.13 (1H, d,J=13.6 Hz), 6.66 (2H, brs), 7.15 (2H, d, J=8.0 Hz), 7.24 (2H, d, J=8.0Hz).

EXAMPLE 251N-(3-Butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and n-butyllithium, the title compoundwas synthesized in the same manner as in Example 241. Yield: 78%.Melting point: 161-162° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J=7.2 Hz), 1.13 (9H, s), 1.30-1.43 (6H,m), 1.49 (3H, s), 1.60-1.79 (3H, m), 1.90-1.99 (1H, m), 2.13 (6H, s),2.24 (2H, s), 6.77 (1H, brs), 7.23 (1H, s).

EXAMPLE 252N-(3-(2-Furyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and furan, the title compound wassynthesized in the same manner as in Example 241. Yield: 88%. Meltingpoint: 108-110° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.96 (3H, s), 1.13 (9H, s), 1.59 (3H, s), 2.17 (3H,s), 2.18 (3H, s), 2.24 (2H, s), 2.59 (1H, brs), 6.35-6.37 (2H, m), 6.79(1H, brs), 7.37 (1H, s), 7.43 (1H, s).

EXAMPLE 253N-(3-(2,4-Dimethoxyphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 1-bromo-2,4-dimethoxybenzene, thetitle compound was synthesized in the same manner as in Example 240.Yield: 62%. Melting point: 150-151° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.91 (3H, s), 1.10 (9H, s), 1.65 (3H, s), 2.12-2.20(8H, m), 3.79 (3H, s), 3.91 (3H, s), 5.03 (1H, brs), 6.43 (1H, dd,J=8.4, 2.4 Hz), 6.52 (1H, d, J=2.4 Hz), 6.92 (1H, brs), 7.05-7.08 (2H,m).

EXAMPLE 254N-(3-(4-Bromophenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 1,4-dibromobenzene, the titlecompound was synthesized in the same manner as in Example 241. Yield:93%. Melting point: 118-119° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.86 (3H, s), 1.10 (9H, s), 1.56 (3H, s), 2.17-2.22(8H, m), 2.44 (1H, brs), 6.80 (1H, brs), 7.10 (1H, s), 7.36 (2H, d,J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz).

EXAMPLE 255N-(3-Hydroxy-3-(4-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 65 and 1-bromo-4-methoxybenzene, the titlecompound was synthesized in the same manner as in Example 240. Yield:72%. Melting point: 110-111° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.84 (3H, s), 1.11 (9H, s), 1.58 (3H, s), 2.18-2.24(9H, m), 3.81 (3H, s), 6.78 (1H, brs), 6.88 (2H, d, J=9.0 Hz), 7.12 (1H,s), 7.40 (2H, d, J=9.0 Hz).

EXAMPLE 256N-(3-Cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 63 and cyclohexylmagnesium bromide, thetitle compound was synthesized in the same manner as in Example 239.Yield: 66%. Melting point: 170-171° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.60-2.10 (30H, m), 2.12 (3H, s), 2.20-2.40 (5H, m),6.55 (1H, br s).

EXAMPLE 257N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(2-pyridyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 63 and 2-bromopyridine, the title compoundwas synthesized in the same manner as in Example 241. Yield: 45%.Melting point: 205-207° C.

¹H-NMR (CDCl₃) δ: 0.89 (3H, s), 1.12 (9H, s), 1.53 (3H, s), 1.64 (3H,s), 2.13 (3H, s), 2.14 (3H, s), 2.25 (2H, s), 6.01 (1H, br s), 6.85 (1H,br s), 7.06 (1H, d, J=6.0 Hz), 7.18-7.24 (1H, m), 7.60 (1H, dt, J=7.8,1.8 Hz), 8.56 (1H, dd, J=7.8, 4.8 Hz).

EXAMPLE 258N-(3-Hydroxy-3-(4-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 63 and 4-bromoanisole, the title compoundwas synthesized in the same manner as in Example 241. Yield: 47%.Melting point: 98-99° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.86 (3H, s), 1.13 (9H, s), 1.51 (3H, s), 1.85 (3H,s), 2.15 (3H, s), 2.16 (3H, s), 2.27 (2H, s), 3.79 (3H, s), 6.59 (H,br), 6.83 (3H, br), 7.38 (1H, br).

EXAMPLE 259N-(3-Hydroxy-3-(3-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 63 and 3-bromoanisole, the title compoundwas synthesized in the same manner as in Example 241. Yield: 46%.Melting point: 154-155° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.89 (3H, s), 1.13 (9H, s), 1.52 (3H, s), 1.87 (3H,s), 2.16 (3H, s), 2.17 (3H, s), 2.27 (2H, s), 3.80 (3H, brs), 6.45 (1H,br), 6.53 (1H, s), 6.75-6.84 (1H, m), 7.20 (2H, br).

EXAMPLE 260N-(3-Hydroxy-3-(4-isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,5,6-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-7-yl)butanamideobtained in Reference Example 64 and 1-bromo-4-isopropylbenzene, thetitle compound was synthesized in the same manner as in Example 240.Yield: 71%. Melting point: 178-179° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.82 (3H, s), 1.14 (9H, s), 1.24 (6H, d, J=6.9 Hz),1.49 (3H, s), 1.91 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.29 (2H, s),2.35 (1H, s), 2.89 (1H, septet, J=6.9 Hz), 6.40-7.80 (5H, m).

EXAMPLE 261 tert-Butyl(3-hydroxy-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 62 and 1-bromo-4-methylbenzene, the titlecompound was synthesized in the same manner as in Example 241.

Yield: 64%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 0.85 (3H, s), 1.20-1.60 (9H, m), 1.50 (3H, s), 1.88(3H, s), 2.15 (3H, s), 2.19 (3H, s), 2.34 (3H, s), 5.77 (1H, br s),6.40-8.20 (4H, m), 1H unidentified.

EXAMPLE 262 tert-Butyl(3-hydroxy-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 62 and 1-iodo-4-isopropylbenzene, thetitle compound was synthesized in the same manner as in Example 241.Yield: 34%. Melting point: 155-157° C. (hexane).

¹H-NMR (CDCl₃) δ: 0.85 (3H, s), 1.24 (6H, d, J=7.0 Hz), 1.20-1.64 (9H,m), 1.52 (3H, s), 1.89 (3H, s), 2.08 (1H, s), 2.16 (3H, s), 2.20 (3H,s), 2.74-3.06 (1H, m), 5.75 (1H, br s), 6.40-8.20 (4H, m).

EXAMPLE 263 tert-Butyl(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Reference Example 62 and 2-bromonaphthalene, the titlecompound was synthesized in the same manner as in Example 241. Yield:50%. Amorphous powder.

¹H-NMR (CDCl₃) δ: 0.90 (3H, br s), 1.20-1.70 (9H, m), 1.57 (3H, s), 1.86(3H, br s), 2.19 (3H, s), 2.22 (3H, s), 2.29 (1H, s), 5.77 (1H, br s),6.60-8.60 (7H, m).

EXAMPLE 264N-(3-(3-Formylphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL, 10.9 mmol) inTHF (20 mL) was added dropwise at −78° C. under an argon atmospheren-butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol), and theresulting mixture was stirred for 30 minutes. To the reaction solutionwas added dropwise at −78° C. a solution of3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide(1.0 g, 3.30 mmol) obtained in Reference Example 65 in THF (10 mL), andthe resulting mixture was stirred for 30 minutes. The reaction solutionwas warmed to room temperature and stirred for 1 hour, and water wasadded to the reaction solution and the product was extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=2:3) to obtain 1.38 g (yield: 92%)ofN-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideas an amorphous powder. To a mixed solution of the obtainedN-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(300 mg, 0.66 mmol) in acetone (4 mL)-water (0.3 mL) was addedpyridinium p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture wasstirred for 30 minutes. The reaction solution was cooled to roomtemperature, and water was added to the reaction solution and theproduct was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue wasrecrystallized from THF-diisopropyl ether to obtain 194 mg (yield: 72%)of the title compound. Melting point: 189-190° C.

¹H-NMR (CDCl₃) δ: 0.86 (3H, s), 1.09 (9H, s), 1.59 (3H, s), 2.18-2.22(8H, m), 2.66 (1H, s), 6.86 (1H, br s), 7.11 (1H, s), 7.52 (1H, t, J=7.5Hz), 7.76 (1H, d, J=7.5 Hz), 7.84 (1H, d, J=7.5 Hz), 7.99 (1H, s), 10.01(1H, s).

EXAMPLE 265N-(3-Hydroxy-3-(3-(hydroxymethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(3-formylphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 264, the title compound was obtained in the samemanner as in Example 21.

Yield: 86%. Melting point: 169-171° C. (THF-diisopropyl ether).

¹H-NMR (CDCl₃) δ: 0.85 (3H, s), 1.09 (9H, s), 1.60 (3H, s), 1.65 (1H,brs), 2.17-2.20 (8H, m), 2.41 (1H, br s), 4.60 (2H, s), 6.85 (1H, br s),7.10 (1H, s), 7.25-7.42 (3H, m), 7.49 (1H, s).

EXAMPLE 266N-(3-Hydroxy-3-(3-(1-hydroxyethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(3-formylphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Reference Example 264 and methylmagnesium bromide, the titlecompound was synthesized in the same manner as in Example 22. Yield:43%. Melting point: 206-207° C. (THF-diisopropyl ether).

¹H-NMR (CDCl₃) δ: 0.85 (3H, s), 1.09 (9H, s), 1.46-1.49 (3H, m), 1.60(3H, s), 2.17-2.21 (9H, m), 2.27 (1H, brs), 4.88 (1H, br s), 6.80 (1H,s), 7.14 (1H, s), 7.30-7.45 (3H, m), 7.52 (1H, s).

EXAMPLE 267N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using5-amino-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-3-olobtained in Reference Example 80, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 59%. Melting point:146-148° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.86 (3H, s), 1.12 (9H, s), 1.51 (3H, s), 1.71 (1H,s), 1.85 (3H, s), 2.16 (6H, s), 2.27 (2H, s), 2.33 (3H, s), 6.60 (1H, brs), 6.82-7.80 (4H, m).

EXAMPLE 268N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using5-amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-olobtained in Reference Example 81, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 82%. Amorphouspowder.

¹H-NMR (CDCl₃) δ: 0.90 (3H, br. s), 1.11 (9H, s), 1.58 (3H, s), 1.83(3H, br. s), 2.19 (6H, s), 2.26 (2H, s), 2.38 (1H, br. s), 6.40-8.60(7H, m), 6.60 (1H, br s).

EXAMPLE 269N-(3-Hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-3-methylbutanamide

Using5-amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-olobtained in Reference Example 81 and 3-methylbutyryl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.

Yield: 32%. Melting point: 108-110° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.80-1.10 (9H, m), 1.50-1.95 (7H, m), 2.05-2.80 (9H,m), 6.65 (1H, br s), 7.00-8.32 (7H, m).

EXAMPLE 270N-(tert-Butyl)-N′-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)urea

Using5-amino-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-3-olobtained in Reference Example 81, the title compound was synthesized inthe same manner as in Example 14. Yield: 74%. Melting point: 212-214° C.(ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.92 (3H, br s), 1.27 (9H, s), 1.60 (3H, s), 1.88 (3H,br s), 2.21 (3H, s), 2.23 (3H, s), 2.44 (1H, br s), 4.12 (1H, br s),5.33 (1H, br. s), 6.60-8.60 (7H, m).

EXAMPLE 2713,3-Dimethyl-N-(2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a solution ofN-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(120 mg, 0.3 mmol) obtained in Example 242 in trifluoroacetic acid (2mL) was added triethylsilane (71 mg, 0.6 mmol) under ice-cooling, andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was added to water and the product was extracted with ethylacetate. The organic layer was washed with an aqueous 1 N sodiumhydroxide solution, water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (ethyl acetate:hexane=1:2)and recrystallized from ethyl acetate-hexane to obtain 93 mg (yield:79%) of the title compound. Melting point: 161-162° C.

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.09 (9H, s), 1.56 (3H, s), 2.15-2.19(8H, m), 2.39 (3H, s), 4.57 (1H, s), 6.60-6.75 (2H, m), 6.91 (1H, s),7.00-7.18 (3H, m).

EXAMPLE 2723,3-Dimethyl-N-(2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-3-(3-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 239, the title compound was synthesized in the samemanner as in Example 271. Yield: 87%. Melting point: 156-157° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.96 (3H, s), 1.09 (9H, s), 1.55 (3H, s), 2.15-2.19(8H, m), 2.31 (3H, s), 4.27 (1H, s), 6.70 (1H, br s), 6.85-6.92 (3H, m),7.04 (1H, d, J=8.4 Hz), 7.16 (1H, t, J=8.4 Hz).

EXAMPLE 273N-(3-(3-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 245, the title compound was synthesized in the samemanner as in Example 271. Yield: 65%. Melting point: 162-163° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.93 (3H, s), 1.09 (9H, s), 1.22 (6H, d, J=6.9 Hz),1.57 (3H, s), 2.15-2.20 (8H, m), 2.86 (1H, septet, J=6.9 Hz), 4.32 (1H,s), 6.72 (1H, br s), 6.90-7.09 (3H, m), 7.08-7.25 (2H, m).

EXAMPLE 274N-(2,2,6,7-Tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 243, the title compound was synthesized in the samemanner as in Example 271. Yield: 82%. Melting point: 182-183° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.09 (9H, s), 1.57 (3H, s), 2.15-2.20(8H, m), 4.32 (1H, s), 6.72 (1H, br s), 6.95 (1H, s), 7.06-7.11 (2H, m),7.23-7.31 (3H, m).

EXAMPLE 275N-(2,2,6,7-Tetramethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 244, the title compound of an oily matter wasobtained in the same manner as in Example 271. Yield: 84%.

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.06 (9H, s), 1.60 (3H, s), 2.16-2.22(8H, m), 4.47 (1H, s), 6.77 (1H, brs), 6.93 (1H, s), 7.18 (1H, dd,J=8.6, 1.6 Hz), 7.42-7.49 (2H, m), 7.58 (1H, br s), 7.73-7.82 (3H, m).

EXAMPLE 276N-(3-(2-Methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(2-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 246, the title compound was synthesized in the samemanner as in Example 271. Yield: 82%. Melting point: 169-170° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.10 (9H, s), 1.57 (3H, s), 2.15-2.19(8H, m), 3.85 (3H, s), 4.82 (1H, s), 6.72 (1H, br s), 6.75-6.91 (4H, m),7.15-7.26 (1H, m).

EXAMPLE 277N-(3-Benzyl-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 249, the title compound was synthesized in the samemanner as in Example 271. Yield: 56%. Melting point: 186-187° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.08 (9H, s), 1.33 (3H, s), 1.37 (3H, s), 2.09 (3H,s), 2.12 (3H, s), 2.17 (2H, s), 2.89 (2H, d, J=7.8 Hz), 3.42 (1H, t,J=7.8 Hz), 6.49 (1H, s), 6.62 (1H, br s), 7.17-7.33 (5H, m).

EXAMPLE 278N-(3-(4-Isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(4-isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 250, the title compound was synthesized in the samemanner as in Example 271. Yield: 63%. Melting point: 130-132° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.10 (9H, s), 1.25 (6H, d, J=6.9 Hz), 1.33 (3H, s),1.43 (3H, s), 2.04 (1H, s), 2.11 (3H, s), 2.14 (3H, s), 2.19 (2H, m),2.86 (1H, septet, J=6.9 Hz), 3.00 (1H, d, J=13.6 Hz), 3.13 (1H, d,J=13.6 Hz), 6.66 (2H, br s), 7.15 (2H, d, J=8.0 Hz), 7.24 (2H, d, J=8.0Hz).

EXAMPLE 279N-(2,2,6,7-Tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 248, the title compound was synthesized in the samemanner as in Example 271. Yield: 65%. Melting point: 137-138° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.05 (3H, s), 1.10 (9H, s), 1.58 (3H, s), 2.15-2.21(8H, m), 4.61 (1H, s), 6.77 (1H, br s), 6.85 (1H, d, J=3.4 Hz), 6.97(1H, dd, J=4.8, 3.4 Hz), 7.10 (1H, s), 7.19 (1H, d, J=4.8 Hz).

EXAMPLE 280N-(2,2,6,7-Tetramethyl-3-(2-(trifluoromethoxy)phenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-(trifluoromethoxy)phenyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 241, the title compound was synthesized in the samemanner as in Example 271. Yield: 47%. Melting point: 155-156° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.11 (9H, s), 1.62 (3H, s), 2.18 (6H,s), 2.22 (2H, s), 3.00 (1H, br s), 6.79 (1H, br s), 7.15-7.36 (5H, m).

EXAMPLE 281N-(3-Butyl-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 251, the title compound was synthesized in the samemanner as in Example 271. Yield: 77%. Melting point: 129-130° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.91 (3H, t, J=7.2 Hz), 1.13 (9H, s), 1.30-1.43 (6H,m), 1.49 (3H, s), 1.60-1.79 (3H, m), 1.90-1.99 (1H, m), 2.13 (6H, s),2.24 (2H, s), 6.77 (1H, br s), 7.23 (1H, s).

EXAMPLE 282N-(3-(2-Furyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(2-furyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 252, the title compound was synthesized in the samemanner as in Example 271. Yield: 67%. Melting point: 126-127° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.06 (3H, s), 1.12 (9H, s), 1.59 (3H, s), 2.12-2.22(8H, m), 4.44 (1H, s), 6.10 (1H, d, J=3.2 Hz), 6.30-6.33 (1H, m), 6.74(1H, br s), 7.10 (1H, s), 7.35-7.36 (1H, m).

EXAMPLE 283N-(2,2,6,7-Tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 240, the title compound was synthesized in the samemanner as in Example 271. Yield: 92%. Melting point: 158-159° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.37 (3H, s), 1.45 (3H, s), 1.86-1.96(2H, m), 2.12 (6H, s), 2.33 (2H, s), 2.65-2.83 (2H, m), 3.03 (1H, t,J=7.8 Hz), 6.73 (1H, br s), 7.17-7.31 (6H, m).

EXAMPLE 284N-(3-(4-Bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-bromophenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 254, the title compound was synthesized in the samemanner as in Example 271. Yield: 88%. Melting point: 171-172° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.10 (9H, s), 1.54 (3H, s), 2.15 (3H,s), 2.18 (3H, s), 2.20 (2H, s), 4.28 (1H, s), 6.72 (1H, br s), 6.94-6.98(3H, m), 7.41 (2H, d, J=8.4 Hz).

EXAMPLE 285N-(3-(4-Methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(4-methoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 255, the title compound was synthesized in the samemanner as in Example 271. Yield: 82%. Melting point: 169-170° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.10 (9H, s), 1.54 (3H, s), 2.14-2.20(8H, m), 3.79 (3H, s), 4.27 (1H, s), 6.71 (1H, br s), 6.82 (2H, d, J=8.7Hz), 6.93 (1H, s), 7.01 (2H, d, J=8.7 Hz).

EXAMPLE 286N-(3-(2,4-(Dimethoxyphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(2,4-(dimethoxyphenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 253, the title compound was synthesized in the samemanner as in Example 271. Yield: 82%. Melting point: 146-147° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.09 (9H, s), 1.55 (3H, s), 2.14-2.19(8H, m), 3.78 (3H, s), 3.82 (3H, s), 4.73 (1H, s), 6.35 (1H, dd, J=8.4,2.4 Hz), 6.45 (1H, d, J=2.4 Hz), 6.66 (1H, d, J=8.4 Hz), 6.76 (1H, brs), 6.90 (1H, s).

EXAMPLE 287N-(3-Cyclohexyl-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 256, the title compound was synthesized in the samemanner as in Example 271. Yield: 48%. Melting point: 198-199° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.50-2.20 (35H, m), 2.24-2.35 (2H, m), 2.67 (1H, d,J=2.7 Hz), 6.55 (1H, br s).

EXAMPLE 2883,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-(2-pyridyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

UsingN-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-pyridyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 257, the title compound was synthesized in the samemanner as in Example 271. Yield: 52%. Melting point: 210-212° C.

¹H-NMR (CDCl₃) δ: 1.04 (3H, s), 1.12 (9H, s), 1.55 (3H, s), 1.79 (3H,s), 2.17 (6H, s), 2.26 (2H, s), 4.41 (1H, s), 6.52 (1H, br s), 6.78 (1H,d, J=7.6 Hz), 7.12 (1H, dd, J=7.6, 4.4 Hz), 7.54-7.61 (1H, m), 8.53 (1H,d, J=4.4 Hz).

EXAMPLE 289N-(3-(4-Methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(4-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 258, the title compound was synthesized in the samemanner as in Example 271. Yield: 40%. Melting point: 175-176° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.12 (9H, s), 1.48 (3H, s), 1.77 (3H,s), 2.15 (6H, s), 2.24 (2H, s), 3.76 (3H, s), 4.08 (1H, s), 6.48 (1H,s), 6.76 (1H, br d, J=5.4 Hz), 6.83 (2H, br).

EXAMPLE 290N-(3-(3-Methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(3-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 259, the title compound was synthesized in the samemanner as in Example 271. Yield: 77%. Melting point: 166-167° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.04 (3H, s), 1.12 (9H, s), 1.49 (3H, s), 1.79 (3H,s), 2.15 (6H, s), 2.25 (2H, s), 3.76 (3H, s), 4.09 (1H, s), 6.25 (1H,br), 6.47 (1H, s), 6.60-6.85 (2H, m), 7.08 (1H, br).

EXAMPLE 291N-(3-(4-Isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-3-(4-isopropylphenyl)-2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamideobtained in Example 260, the title compound was synthesized in the samemanner as in Example 271. Yield: 53%. Melting point: 152-153° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.14 (9H, s), 1.21 (6H, d, J=6.9 Hz),1.46 (3H, s), 1.83 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 2.29 (2H, s),2.85 (1H, septet, J=6.9 Hz), 4.11 (1H, s), 6.40-7.15 (5H, m).

EXAMPLE 292N-(3-(4-Formylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(500 mg, 1.13 mmol) obtained in Example 284 in THF (10 mL) was addeddropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 Mhexane solution, 1.56 mL, 2.48 mmol), and the mixture was stirred for 30minutes. DMF (90 mg, 1.24 mmol) was added to the reaction solution atthe same temperature, and the mixture was stirred for 30 minutes, warmedto room temperature, and stirred for 1 hour. Water was added to thereaction solution and the product was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethylacetate:hexane=2:3) and recrystallized from ethyl acetate-hexane toobtain 204 mg (yield: 46%) of the title compound. Melting point:169-170° C.

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 1.09 (9H, s), 1.58 (3H, s), 2.04-2.20(8H, m), 4.38 (1H, s), 6.74 (1H, br s), 6.99 (1H, s), 7.25 (2H, d, J=8.4Hz), 7.81 (2H, dd, J=8.4 Hz), 9.99 (1H, s).

EXAMPLE 293N-(3-(4-Acetylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 284 and N,N-dimethylacetamide, the title compoundwas synthesized in the same manner as in Example 292. Yield: 20%.Melting point: 195-196° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.96 (3H, s), 1.09 (9H, s), 1.57 (3H, s), 2.16-2.19(8H, m), 2.59 (3H, s), 4.36 (1H, s), 6.73 (1H, br s), 6.97 (1H, s), 7.18(2H, d, J=8.0 Hz), 7.88 (2H, d, J=8.0 Hz).

EXAMPLE 294N-(3-(4-(Hydroxymethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-formylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 292, the title compound was synthesized in the samemanner as in Example 21. Yield: 80%. Melting point: 162-163° C.(THF-diisopropyl ether).

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.09 (9H, s), 1.56 (3H, s), 1.65 (1H, t,J=6.0 Hz), 2.15-2.19 (8H, m), 4.32 (1H, s), 4.67 (2H, d, J=6.0 Hz), 6.72(1H, br s), 6.94 (1H, s), 7.09 (2H, d, J=8.0 Hz), 7.29 (2H, d, J=8.0Hz).

EXAMPLE 295N-(3-(4-(1-Hydroxyethyl)phenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-(4-acetylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 293, the title compound of an oily matter wassynthesized in the same manner as in Example 21. Yield: 65%.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.09 (9H, s), 1.48 (3H, d, J=6.4 Hz),1.55 (3H, s), 1.66 (1H, brs), 2.14-2.19 (8H, m), 4.30 (1H, s), 4.87 (1H,q, J=6.4 Hz), 6.79 (1H, br s), 6.93 (1H, s), 7.07 (2H, d, J=8.0 Hz),7.29 (2H, d, J=8.0 Hz).

EXAMPLE 296N-(3-(2-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution of 1-bromo-2-isopropylbenzene (1.20 g, 6.03 mmol) in THF (5mL) was added dropwise under an argon atmosphere to a mixture ofmagnesium (147 mg, 6.03 mmol) and a catalytic amount of iodine, and themixture was stirred at 70° C. for 30 minutes. To the reaction solutionwas added dropwise a solution of3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide(350 mg, 1.15 mmol) obtained in Reference Example 65 in THF (3 mL), andthe mixture was refluxed with heating for 12 hours. The reactionsolution was added to ice and the product was extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:2) to obtain 79 mg (yield: 16%)ofN-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide.To a solution of the compound (79 mg, 0.19 mmol) in trifluoroacetic acid(1 mL) was added with ice-cooling triethylsilane (44 mg, 0.38 mmol), andthe mixture was stirred at room temperature for 1 hour. The reactionsolution was added to water and the product was extracted with ethylacetate. The organic layer was washed with an aqueous 1 N sodiumhydroxide solution, water and saturated brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethylacetate:hexane=1:2) to obtain 39 mg (yield: 51%) of the title compound.Yield: 51%. Melting point: 188-189° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.01 (3H, s), 1.09 (9H, s), 1.27 (3H, d, J=7.0 Hz),1.32 (3H, d, J=7.0 Hz), 1.57 (3H, s), 2.15-2.20 (8H, m), 3.15-3.30 (1H,m), 4.67 (1H, s), 6.67 (1H, d, J=7.8 Hz), 6.69 (1H, br s), 6.88 (1H, s),7.02 (1H, t, J=7.8 Hz), 7.17 (1H, t, J=7.8 Hz), 7.29 (1H, d, J=7.8 Hz).

EXAMPLE 2973,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-piperidin-1-yl-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a solution ofN-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(450 mg, 1.41 mmol) obtained in Example 234 in dichloromethane (3 mL)was added triethylamine (0.79 mL, 5.64 mmol), and then added dropwisewith ice-cooling methanesulfonyl chloride (0.22 mL, 2.82 mmol). Thereaction solution was stirred for 30 minutes, and to the reactionsolution was added piperidine (0.70 mL, 7.05 mmol), and the mixture wasstirred at room temperature for 16 hours. Water was added to thereaction solution and the product was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane ethyl acetate=20:1) to obtain 270 mg (yield: 50%) of the titlecompound. Melting point: 229-230° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.10-1.82 (22H, m), 2.08 (3H, s), 2.12 (3H, s), 2.18(3H, s), 2.22-2.43 (3H, m), 2.78 (1H, br s), 2.95 (1H, br s), 3.68 (1H,s), 6.56 (1H, s)

EXAMPLE 2983,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-pyrrolidin-1-yl-2,3-dihydro-1-benzofuran-5-yl)butanamide

UsingN-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 234 and pyrrolidine, the title compound wassynthesized in the same manner as in Example 297. Yield: 36%. Meltingpoint: 197-198° C. (ethyl acetate-hexane). ¹H-NMR (CDCl₃) δ: 1.16 (9H,s), 1.23 (3H, s), 1.49 (3H, s), 1.58-1.72 (4H, m), 2.09 (3H, s), 2.13(6H, s), 2.30 (2H, s), 2.48-2.80 (4H, m), 4.02 (1H, s), 6.55 (1H, br s).

EXAMPLE 299N-(3-Anilino-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 235 and aniline, the title compound was synthesizedin the same manner as in Example 297. Yield: 79%. Melting point:151-152° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.37 (3H, s), 1.53 (3H, s), 2.14 (6H,s), 2.22 (2H, s), 3.93 (1H, d, J=8.7 Hz), 4.81 (1H, d, J=8.7 Hz), 6.60(2H, d, J=7.8 Hz), 6.67-6.75 (2H, m), 7.17 (3H, t, J=7.8 Hz).

EXAMPLE 300N-(3-((2-Methoxyphenyl)amino)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 235 and (2-methoxyphenyl)amine, the title compoundwas synthesized in the same manner as in Example 297. Yield: 75%.Melting point: 184-185° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.34 (3H, s), 1.53 (3H, s), 2.14 (6H,s), 2.22 (2H, s), 3.78 (3H, s), 4.53 (1H, d, J=8.1 Hz), 4.86 (1H, d,J=8.1 Hz), 6.63-6.68 (2H, m), 6.75-6.77 (2H, m), 6.86 (1H, t, J=9.0 Hz),7.16 (1H, s).

EXAMPLE 301N-(3-((2-(Trifluoromethoxy)phenyl)amino)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 235 and (2-(trifluoromethoxy)phenyl)amine, the titlecompound was synthesized in the same manner as in Example 297. Yield:73%. Melting point: 196-197° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.35 (3H, s), 1.54 (3H, s), 2.15 (6H,s), 2.23 (2H, s), 4.32 (1H, d, J=9.0 Hz), 4.85 (1H, d, J=9.0 Hz), 6.67(1H, t, J=6.9 Hz), 6.70-6.80 (2H, m), 7.12-7.17 (3H, m).

EXAMPLE 302 tert-Butyl(7-bromo-2,2,4,6-tetramethyl-3-(pyrrolidin-1-yl)-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 236 and pyrrolidine, the title compound wassynthesized in the same manner as in Example 297.

Yield: 43%. Melting point: 128-130° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.28-1.57 (15H, m), 1.60-1.70 (4H, m), 2.14 (3H, s),2.33 (3H, s), 2.40-2.67 (2H, m) 2.70-2.80 (2H, m), 4.13 (1H, s), 5.82(1H, br s).

EXAMPLE 303 tert-Butyl(7-bromo-3-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 236 and dimethylamine, the title compound wassynthesized in the same manner as in Example 297. Yield: 89%. Meltingpoint: 111-112° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.27 (3H, s), 1.36-1.60 (12H, m), 2.04-2.60 (12H, m),3.86 (1H, s), 5.84 (1H, b rs).

EXAMPLE 304 tert-Butyl(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 120, the title compound was synthesized inthe same manner as in Reference Example 59. Yield: 24%. Melting point:119-120° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.21 (6H, d, J=6.6 Hz), 1.25-1.58 (12H,m), 1.81 (3H, s), 2.16 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J=6.9Hz), 4.08 (1H, s), 5.72 (1H, s), 6.64-7.10 (4H, m).

EXAMPLE 305 tert-Butyl(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 122, the title compound was synthesized inthe same manner as in Reference Example 59. Yield: 18%. Melting point:124-125° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.01 (3H, s), 1.20-1.64 (9H, m), 1.48 (3H, s), 1.80(3H, s), 2.16 (3H, s), 2.17 (3H, s), 2.30 (3H, s), 4.08 (1H, s), 5.71(1H, br s), 6.20-7.60 (4H, m).

EXAMPLE 306N-(7-(4-Isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of tert-butyl(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate(1.77 g, 4.78 mmol) obtained in Example 238 in THF (20 mL) was addeddropwise at −78° C. under argon atmosphere n-butyllithium (1.60 M hexanesolution, 6.25 mL, 10.0 mmol), and the mixture was stirred for 30minutes. To the reaction solution was added dropwise at −78° C. asolution of 4-isopropylbenzaldehyde (815 mg, 5.50 mmol) in THF (5 mL).The reaction solution was warmed to room temperature and stirred for 1hour. Water was added to the reaction solution and the product wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain1.20 g (yield: 59%) of tert-butyl(7-(hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate.To a mixture of the compound (1.00 g, 2.27 mmol) in trifluoroacetic acid(5 mL) was added with ice-cooling triethylsilane (1.0 mL, 6.4 mmol), andthe mixture was stirred at room temperature for 1 hour. After thereaction solution was concentrated under reduced pressure, to theresidue was added an aqueous saturated sodium hydrogen carbonatesolution and the aqueous layer was made alkaline, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain a crude product of7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine.To a solution of the compound (330 mg, about 1.02 mmol) andtert-butylacetyl chloride (0.16 mL, 1.12 mmol) in dichloromethane (30mL) was added triethylamine (0.16 mL, 1.12 mmol) at room temperature,and the mixture was stirred at room temperature for 1 hour. Water wasadded to the reaction solution, the organic layer was separated, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were washed with 1 N hydrochloric acid and an aqueous saturatedsodium hydrogen carbonate solution, dried over magnesium sulfate,filtered, and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=4:1) to obtain 273 mg (yield: 17%) of the title compound.Melting point: 170-171° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.19 (6H, d, J=7.2 Hz), 1.46 (6H, s),2.05 (3H, s), 2.08 (3H, s), 2.25 (2H, s), 2.82 (1H, septet, J=7.2 Hz),2.96 (2H, s), 3.89 (2H, s), 6.46 (1H, br s), 7.04 (2H, d, J=8.1 Hz),7.09 (2H, d, J=8.1 Hz).

EXAMPLE 307N-(7-(4-Isopropylbenzyl)-2,2,4,6-tetramethyl-3-(pyrrolidin-1-yl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using tert-butyl(7-bromo-2,2,4,6-tetramethyl-3-(pyrrolidin-1-yl)-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 302, the title compound was synthesized in the samemanner as in Example 306. Yield: 61%. Melting point: 179-180° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.18 (3H, s), 1.21 (3H, s), 1.25 (3H,s), 1.49 (3H, s), 1.62-1.72 (4H, m), 2.05 (3H, s), 2.14 (3H, s), 2.25(2H, dd, J=17.1, 13.2 Hz), 2.59 (2H, br), 2.70-2.90 (3H, m), 3.80-3.95(2H, br), 4.05 (1H, s), 6.48 (1H, s), 7.00-7.10 (4H, m).

EXAMPLE 308N-(3-(Dimethylamino)-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using tert-butyl(7-bromo-3-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 303, the title compound was synthesized in the samemanner as in Example 306. Yield: 33%. Melting point: 138-139° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.18 (3H, s), 1.21 (3H, s), 1.24 (3H,s), 1.51 (3H, s), 2.03-2.06 (14H, m), 2.70-2.88 (1H, m), 3.78 (1H, s),3.90 (2H, br s), 6.49 (1H, s), 6.98-7.05 (4H, m).

EXAMPLE 309N-(2,2,6,7-Tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using2,2,6,7-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 139, the title compound (yield: 88%) wasobtained in the same manner as in Reference Example 63. Amorphouspowder.

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.08 (9H, s), 1.54 (3H, s), 2.14 (3H,s), 2.17 (5H, s), 2.32 (3H, s), 4.28 (1H, s), 6.75 (1H, brs), 6.90 (1H,s), 6.96 (2H, d, J=7.9 Hz), 7.08 (2H, d, J=7.9 Hz).

EXAMPLE 310N-(2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 122 and butyryl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.

Yield: 50%. Melting point: 138-139° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.74-2.41 (25H, m), 4.10 (1H, s), 6.54 (1H, br s),7.03 (4H, br s).

EXAMPLE 311N-(2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)pentanamide

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 122 and pentanoyl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.

Yield: 62%. Melting point: 156-157° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.78-2.43 (27H, m), 4.10 (1H, s), 6.55 (1H, br s),7.04 (4H, br s).

EXAMPLE 312N-(2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)hexanamide

Using2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 122 and hexanoyl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.

Yield: 52%. Melting point: 96-97° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.77-2.41 (29H, m), 4.10 (1H, s), 6.55 (1H, br s),7.03 (4H, br s).

EXAMPLE 313N-(3-(4-Fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 123, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 60%. Melting point:194-195° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.12 (9H, s), 1.49 (3H, s), 1.77 (3H,s), 2.15 (6H, s), 2.25 (2H, s), 4.11 (1H, s), 6.40-7.20 (5H, m).

EXAMPLE 3143,3-Dimethyl-N-(2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 121, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 55%. Melting point:214-215° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.92-1.20 (12H, m), 1.50 (3H, s), 1.77 (3H, s), 2.16(6H, s), 2.25 (2H, s), 4.13 (1H, s), 6.40-7.38 (6H, m).

EXAMPLE 315N-(3-(4-Bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-bromophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 124, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 65%. Melting point:201-202° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.92-1.18 (12H, m), 1.49 (3H, s), 1.76 (3H, s), 2.15(6H, s), 2.25 (2H, s), 4.09 (1H, s), 6.51-7.44 (5H, m).

EXAMPLE 316N-(3-(4-tert-Butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of3-(4-tert-butylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride obtained in Reference Example 76 (400 mg, 1.16 mmol) andtert-butylacetyl chloride (0.17 mL, 1.22 mmol) in dichloromethane (10mL) was added triethylamine (0.35 mL, 2.50 mmol) at room temperature,and the mixture was stirred at room temperature for 1 hour. Water wasadded to the reaction solution, the organic layer was separated, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were washed with 1 N hydrochloric acid and an aqueous saturatedsodium hydrogen carbonate solution, dried over magnesium sulfate,filtered, and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane:ethylacetate=8:1) to obtain 110 mg (yield: 41%) of the title compound.Amorphous substance.

¹H-NMR (CDCl₃) δ: 0.99 (3H, s), 1.06 (9H, s), 1.12 (9H, s), 1.49 (3H,s), 1.78 (3H, s), 2.16 (6H, s), 2.25 (2H, s), 4.10 (1H, s), 6.50 (1H, brs), 6.70-7.24 (4H, m).

EXAMPLE 317N-(3-(4-Isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride obtained in Reference Example 74, the title compound wassynthesized in the same manner as in Example 316. Yield: 38%. Meltingpoint: 172-173° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.94 (3H, s), 1.06 (9H, s), 1.23 (6H, d, J=6.9 Hz),1.55 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.19 (2H, s), 2.87 (1H,septet, J=6.6 Hz), 4.29 (1H, s), 6.71 (1H, br s), 6.94 (1H, s), 7.00(2H, d, J=7.8 Hz), 7.13 (2H, d, J=7.8 Hz).

EXAMPLE 318N-(3-(4-Isopropylphenyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride obtained in Reference Example 75, the title compound wassynthesized in the same manner as in Example 316. Yield: 23%. Meltingpoint: 118-119° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.01 (3H, s), 1.10 (9H, s), 1.21 (6H, d, J=6.9 Hz),1.48 (3H, s), 1.78 (3H, s), 2.19 (2H, s), 2.21 (3H, s), 2.85 (1H,septet, J=6.9 Hz), 4.08 (1H, s), 6.52-7.24 (6H, m)

EXAMPLE 319N-(3-(4-Isopropylphenyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 78, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 52%. Amorphoussubstance.

¹H-NMR (CDCl₃) δ: 1.00 (3H, s), 1.11 (9H, s), 1.21 (6H, d, J=6.9 Hz),1.49 (3H, s), 1.79 (3H, s), 2.21 (3H, s), 2.23 (2H, s), 2.84 (1H,septet, J=6.9 Hz), 4.08 (1H, s), 6.53 (1H, br s), 6.56 (1H, s),6.70-7.10 (4H, m).

EXAMPLE 320N-(3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 86, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 52%. Melting point:126-127° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.96 (3H, s), 1.07 (9H, s), 1.24 (6H, d, J=6.6 Hz),1.56 (3H, s), 2.12 (2H, s), 2.88 (1H, septet, J=6.6 Hz), 4.29 (1H, s),6.75 (1H, d, J=8.1 Hz), 6.91 (1H, br s), 6.99 (2H, d, J=8.1 Hz), 7.14(2H, d, J=8.1 Hz), 7.16-7.25 (2H, m).

EXAMPLE 321N-(3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 86 and butyryl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.Yield: 27%. Amorphous substance.

¹H-NMR (CDCl₃) δ: 0.97 (3H, s), 0.98 (3H, t, J=7.2 Hz), 1.24 (6H, d,J=6.9 Hz), 1.56 (3H, s), 1.60-1.80 (2H, m), 2.26 (2H, t, J=7.5 Hz), 2.88(1H, septet, J=6.9 Hz), 4.29 (1H, s), 6.75 (1H, d, J=9.3 Hz), 6.90-7.05(3H, m), 7.13 (2H, d, J=8.1 Hz), 7.17-7.22 (2H, m).

EXAMPLE 322N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 120 and butyryl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.

Yield: 59%. Melting point: 120-122° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.78-1.10 (6H, m), 1.21 (6H, d, J=6.9 Hz), 1.60-1.90(8H, m), 2.10-2.40 (8H, m), 2.84 (1H, septet, J=6.9 Hz), 4.10 (1H, s),6.50-7.20 (5H, m).

EXAMPLE 323N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)pentanamide

Using3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 120 and pentanoyl chloride, the titlecompound was synthesized in the same manner as in Reference Example 63.

Yield: 44%. Melting point: 106-107° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.70-1.90 (22H, m), 2.05-2.41 (8H, m), 2.84 (1H,septet, J=6.6 Hz), 4.10 (1H, s), 6.42-7.18 (5H, m).

EXAMPLE 324N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amineobtained in Reference Example 120, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 41%. Amorphoussubstance.

¹H-NMR (CDCl₃) δ: 0.90-1.20 (12H, m), 1.21 (6H, d, J=7.2 Hz), 1.48 (3H,s), 1.78 (3H, s), 2.15-2.27 (8H, m), 2.84 (1H, septet, J=7.2 Hz), 4.09(1H, s), 6.40-7.10 (5H, m).

EXAMPLE 325N-(3-(4-Isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amineobtained in Reference Example 77, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 50%. Melting point:128-129° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.02 (3H, s), 1.17 (9H, s), 1.21 (6H, d, J=6.9 Hz),1.48 (3H, s), 1.83 (3H, s), 2.04 (3H, s), 2.12 (3H, s), 2.31 (2H, s),2.84 (1H, septet, J=7.2 Hz), 4.10 (1H, s), 6.50-7.18 (5H, m).

EXAMPLE 326N-(3-Benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl)-3,3-dimethylbutanamide

Using 3-benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amineobtained in Reference Example 79, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 38%. Melting point:209-210° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.26 (3H, s), 1.40 (3H, s), 1.80 (3H,s), 2.01 (3H, s), 2.07 (3H, s), 2.29 (2H, s), 2.75 (1H, dd, J=14.7, 6.0Hz), 2.89 (1H, dd, J=14.7, 8.4 Hz), 3.29 (1H, dd, J=8.4, 6.0 Hz), 6.60(1H, br s), 7.10-7.30 (5H, m).

EXAMPLE 327N-(3-(4-Isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amineobtained in Reference Example 96, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 51%. Melting point:64-68° C. (hexane).

¹H-NMR (CDCl₃) δ: 0.95 (3H, s), 1.12 (9H, s), 1.24 (6H, d, J=6.9 Hz),1.57 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.89 (1H, septet, J=6.9 Hz),4.30 (1H, s), 6.59 (1H, s), 6.99 (2H, d, J=8.1 Hz), 7.14 (2H, d, J=8.1Hz), 7.17 (1H, br s), 7.98 (1H, s).

EXAMPLE 328N-(3-(4-Isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amineobtained in Reference Example 97, the title compound was synthesized inthe same manner as in Reference Example 63. Yield: 67%. Melting point:140-141° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.96 (3H, s), 1.14 (9H, s), 1.22 (6H, d, J=6.9 Hz),1.47 (3H, s), 1.83 (3H, s), 2.20 (3H, s), 2.28

(2H, s), 2.85 (1H, septet, J=6.9 Hz), 3.64 (3H, s), 4.10

(1H, s), 6.40-7.18 (5H, m).

EXAMPLE 329N-(3-(4-Isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-N,3,3-trimethylbutanamide

To a solution ofN-(3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(110 mg, 290 mmol) obtained in Example 320 in DMF (3 mL) was addedsodium hydride (a 60% dispersion in liquid paraffin, 12.8 mg, 319 mmol)at 0° C. and the mixture was stirred at room temperature for 30 minutes.Methyl iodide (8.0 g, 319 mmol) was added to the reaction solution andthe mixture was stirred at room temperature for 30 minutes. Water wasadded to the reaction solution and the product was extracted withdiisopropyl ether. The combined extracts were washed with water, driedover magnesium sulfate, and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane:ethyl acetate=4:1) to obtain 47 mg (yield: 41%) of the titlecompound. Melting point: 78-79° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 0.93 (9H, s), 1.00 (3H, s), 1.24 (6H, d, J=7.0 Hz),1.62 (3H, s), 1.94-2.10 (2H, m), 2.90 (1H, septet, J=7.0 Hz), 3.19 (3H,s), 4.36 (1H, s), 6.77-6.92 (3H, m), 6.98 (2H, d, J=8.0 Hz), 7.16 (2H,d, J=8.0 Hz).

EXAMPLE 330N-(3-(4-Isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(4-morpholinyl)propionamidehydrochloride

To a solution of3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine(350 mg, 1.08 mmol) obtained in Reference Example 120 and3-chloropropionyl chloride (0.39 mL, 3.72 mmol) in dichloromethane (15mL) was added triethylamine (0.18 mL, 1.30 mmol) at room temperature andthe mixture was stirred at room temperature for 1 hour. Water was addedto the reaction solution, the organic layer was separated, and theaqueous layer was extracted with dichloromethane. The combined organiclayers were washed with 1 N hydrochloric acid and an aqueous saturatedsodium hydrogen carbonate solution, dried over magnesium sulfate,filtered, and then concentrated under reduced pressure to obtain a crudeproduct ofN-(3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3-chloropropionamide.A mixture of the compound, morpholine and potassium carbonate in ethanolwas refluxed with heating for 16 hours. The mixture was poured intowater and the product was extracted with ethyl acetate. The organiclayer was washed with water, dried over magnesium sulfate, filtered, andthen concentrated under reduced pressure. The obtained residue waspurified by basic silica gel column chromatography (hexane:ethylacetate=10:1) to obtain a free base of the title compound. The compoundwas crystallized from 4 N hydrochloric acid-ethyl acetate to obtain 230mg (yield: 42%) of the title compound. Melting point: 158-161° C.(methanol-diethyl ether).

¹H-NMR (DMSO-d₆) δ: 0.94 (3H, s), 1.17 (6H, d, J=6.9 Hz), 1.43 (3H, s),1.66 (3H, s), 2.02 (3H, s), 2.09 (3H, s), 2.77-2.98 (3H, m), 3.08-3.18(2H, m), 3.25-3.47 (4H, m), 3.80 (2H, t, J=12.0 Hz), 3.94 (2H, d, J=11.4Hz), 4.18 (1H, s), 4.42 (1H, br s), 6.60-7.20 (4H, m), 9.35 (1H, s).

EXAMPLE 331 tert-Butyl(2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using 2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained inReference Example 304, the title compound was synthesized in the samemanner as in Reference Example 59. The yield was quantitative. Oilymatter.

¹H-NMR (CDCl₃) δ: 1.43 (3H, d, J=6.3 Hz), 1.45 (9H, s), 2.12 (3H, s),2.19 (3H, s), 2.69 (1H, dd, J=7.5, 15.0 Hz), 3.21 (1H, dd, J=8.7, 15.0Hz), 4.80-4.97 (1H, m), 5.72 (1H, br s), 6.46 (1H, s).

EXAMPLE 332 tert-Butyl(7-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained inExample 331, the title compound was synthesized in the same manner as inReference Example 66. Yield: 75%. Melting point: 115-116° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.35-1.58 (12H, m), 2.10 (3H, s), 2.31 (3H, s), 2.82(1H, dd, J=7.5, 15.0 Hz), 3.34 (1H, dd, J=8.7, 15.0 Hz), 4.96-5.08 (1H,m), 5.83 (1H, br s).

EXAMPLE 333 tert-Butyl(7-(hydroxy(4-isopropylphenyl)methyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate

Using tert-butyl(7-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 332, the title compound was synthesized in the samemanner as in Reference Example 82. Yield: 71%. Melting point: 141-142°C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.21 (6H, d, J=6.9 Hz), 1.38 (3H, d, J=6.0 Hz), 1.49(9H, s), 2.14 (6H, s), 2.71 (1H, dd, J=7.5, 15.0 Hz), 2.80-2.90 (1H,septet, J=6.9 Hz), 3.24 (1H, dd, J=8.7, 15.0 Hz), 4.07 (1H, br d, J=9.9Hz), 4.93-5.08 (1H, m), 5.75 (1H, br s), 5.90 (1H, d, J=9.9 Hz), 7.13(2H, d, J=8.1 Hz), 7.27 (2H, d, J=8.1 Hz).

EXAMPLE 334N-(7-(4-Isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using tert-butyl(7-(hydroxy(4-isopropylphenyl)methyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamateobtained in Example 333, the title compound was synthesized in the samemanner as in Example 224. Yield: 32%. Melting point: 179-180° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.44 (3H, d,J=6.0 Hz), 2.06 (3H, s), 2.10 (3H, s), 2.26 (2H, s), 2.71-2.90 (2H, m),3.27 (1H, dd, J=8.7, 15.0 Hz), 3.91 (2H, s), 4.80-4.97 (1H, m), 6.49(1H, br s), 7.07 (4H, s).

EXAMPLE 335N-(2-(Hydroxymethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(4-hydroxy-3-(4-isopropylbenzyl)-2,6-dimethyl-5-(2-methylprop-2-en-1-yl)phenyl)-3,3-dimethylbutanamide(300 mg, 0.71 mmol) obtained in Reference Example 341 in dichloromethane(2 mL) were added with ice-cooling an aqueous saturated sodium hydrogencarbonate solution (1 mL) and m-chloroperbenzoic acid (302 mg, 1.75mmol). The reaction solution was stirred at room temperature for 1 hour.Water was added to the reaction solution and the product was extractedwith ethyl acetate.

The combined organic layers were washed with a 10% aqueous sodiumsulfite solution and saturated aqueous sodium bicarbonate solution,dried over anhydrous sodium sulfate, filtered, and then concentratedunder reduced pressure.

The residue was purified by silica gel column chromatography (ethylacetate:hexane=3:2) to obtain 61 mg (yield: 20%) of the title compound.Melting point: 186-187° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.42 (3H, s),2.09 (6H, s), 2.27 (2H, s), 2.76-2.90 (2H, m), 3.14 (1H, d, J=15.0 Hz),3.56 (2H, m), 3.87 (1H, d, J=15.6 Hz), 3.93 (1H, d, J=15.6 Hz), 6.49(1H, br s), 7.06 (2H, d, J=8.1 Hz), 7.09 (2H, d, J=8.1 Hz), 1Hunidentified.

EXAMPLE 336N-(2-(Iodomethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A solution ofN-(4-hydroxy-3-(4-isopropylbenzyl)-2,6-dimethyl-5-(2-methylprop-2-en-1-yl)phenyl)-3,3-dimethylbutanamide(300 mg, 0.71 mmol) obtained in Reference Example 341,benzyltrimethylammonium iododichloride (272 mg, 0.78 mmol) and calciumcarbonate (92 mg, 0.92 mmol) in THF (5 mL)-methanol (5 mL) was stirredat room temperature for 12 hours. Water and an aqueous saturated sodiumhydrogen carbonate solution were added to the reaction solution and theproduct was extracted with ethyl acetate. The organic layer was washedwith a 10% aqueous sodium sulfite solution and saturated aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure to obtain 380 mg (yield: 98%)of the title compound. Oily matter.

¹H-NMR (CDCl₃) δ: 1.04 (9H, s), 1.19 (6H, d, J=6.9 Hz), 1.65 (3H, s),2.03 (3H, s), 2.06 (3H, s), 2.21 (2H, s), 2.84 (1H, septet, J=6.9 Hz),2.98 (1H, d, J=15.6 Hz), 3.26 (1H, d, J=15.6 Hz), 3.41 (2H, s), 3.87(2H, s), 6.68 (1H, br s), 7.05 (2H, d, J=8.1 Hz), 7.10 (2H, d, J=8.1Hz).

EXAMPLE 337N-(7-(4-Isopropylbenzyl)-2,4,6-trimethyl-2-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixture ofN-(2-(iodomethyl)-7-(4-isopropylbenzyl)-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(102 mg, 0.19 mmol) obtained in Example 336 and pyrrolidine (1.5 mL) wasreacted using a microwave reactor (110° C., hold time 20 min, 250 W).Water was added to the reaction solution and the product was extractedwith ethyl acetate. The combined organic layers were washed with waterand saturated brine, dried over anhydrous sodium sulfate, filtered, andthen concentrated under reduced pressure to obtain 86 mg (yield: 95%) ofthe title compound. Melting point: 143-144° C. (THF-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.19 (6H, d, J=6.9 Hz), 1.43 (3H, s),1.50-1.75 (4H, m), 2.07 (3H, s), 2.09 (3H, s), 2.26 (2H, s), 2.42-2.63(4H, m), 2.69 (2H, s), 2.73-2.90 (2H, m), 3.23 (1H, d, J=15.0 Hz), 3.84(1H, d, J=15.3 Hz), 3.92 (1H, d, J=15.3 Hz), 6.47 (1H, br s), 7.03 (2H,d, J=8.1 Hz), 7.07 (2H, d, J=8.1 Hz).

EXAMPLE 3383,3-Dimethyl-N-(3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

Using3,3-dimethyl-N-(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Reference Example 342, the title compound was synthesized inthe same manner as in Example 234. Yield: 82%. Melting point: 217-218°C. (THF-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.30 (3H, s), 1.49 (3H, s), 1.78 (1H, d,J=9.0 Hz), 2.19 (3H, s), 2.25 (3H, s), 2.28 (2H, s), 4.69 (1H, d, J=9.0Hz), 6.51 (1H, s), 6.57 (1H, br s).

EXAMPLE 3393,3-Dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide

To a mixed solution of3,3-dimethyl-N-(3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamide(2.0 g, 6.55 mmol) obtained in Example 338 in trifluoroacetic acid (3mL) was added dropwise with ice-cooling triethylsilane (2.09 g, 13.10mmol). The reaction solution was warmed to room temperature and stirredfor 30 minutes. Water was added to the reaction solution and the productwas extracted with ethyl acetate. The combined organic layers werewashed with an aqueous 1 N sodium hydroxide solution and an aqueoussaturated sodium hydrogen carbonate solution, dried over anhydroussodium sulfate, filtered, and then concentrated under reduced pressureto obtain 1.75 g (yield: 92%) of the title compound. Melting point:181-182° C. (THF-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.46 (6H, s), 2.08 (3H, s), 2.17 (3H,s), 2.27 (2H, s), 2.91 (2H, s), 6.45 (1H, s), 6.48 (1H, br s).

EXAMPLE 340N-(7-Formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Example 339, the title compound was synthesized in the samemanner as in Example 20. Yield: 85%. Melting point: 180-181° C.(THF-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.52 (6H, s), 2.13 (3H, s), 2.20 (2H,s), 2.47 (3H, s), 2.92 (2H, s), 6.54 (1H, br s), 10.33 (1H, s).

EXAMPLE 341N-(7-(Hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a mixture of magnesium (198 mg, 8.13 mmol) and a catalytic amount ofiodine was added dropwise under argon atmosphere a solution of1-bromo-4-isopropylbenzene (1.62 g, 8.13 mmol) in THF (5 mL) under argonatmosphere at room temperature, and the reaction solution was heateduntil the color of iodine disappeared. To the reaction solution wasadded dropwise at room temperature a solution ofN-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 340 (860 mg, 2.71 mmol) in THF (5 mL) and themixture was stirred for 1 hour. Water was added to the reaction solutionand the product was extracted with ethyl acetate.

The combined organic layers were washed with saturated brine, dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure to synthesize 1.15 g (yield: 97%) of the title compound.Amorphous powder.

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.21 (6H, d, J=6.9 Hz), 1.42 (3H, s),1.49 (3H, s), 2.07 (3H, s), 2.10 (3H, s), 2.27 (2H, s), 2.85 (1H,septet, J=6.9 Hz), 2.92 (2H, s), 4.17 (1H, d, J=10.2 Hz), 5.86 (1H, d,J=10.2 Hz), 6.59 (1H, br s), 7.11 (2H, d, J=8.1 Hz), 7.25 (2H, d, J=8.1Hz).

EXAMPLE 342N-(7-(4-Isopropylbenzoyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution ofN-(7-(hydroxy(4-isopropylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(209 mg, 0.48 mmol) obtained in Example 341 in dichloromethane (7 mL)was added manganese dioxide (415 mg, 4.8 mmol) and the mixture wasstirred at room temperature for 8 hours. The reaction solution wasfiltered and the filtrate was concentrated. The obtained residue waspurified by silica gel column chromatography (ethyl acetate:hexane=2:3)to obtain 156 mg (yield: 75%) of the title compound. Melting point:194-195° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.26 (6H, d, J=7.0 Hz), 1.35 (6H, s),2.00 (3H, s), 2.14 (3H, s), 2.30 (2H, s), 2.84-3.05 (3H, m), 6.62 (1H,br s), 7.25 (2H, d, J=8.0 Hz), 7.80 (2H, d, J=8.0 Hz).

EXAMPLE 343N-(7-Bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)butanamideobtained in Example 339, the title compound was synthesized in the samemanner as in Reference Example 66. Yield: 85%. Melting point: 205-206°C. (methanol).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.51 (6H, s), 2.05 (3H, s), 2.28 (2H,s), 2.28 (3H, s), 3.02 (2H, s), 6.58 (1H, br s).

EXAMPLE 344N-(7-(4-Isopropylphenoxy)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

A mixed solution ofN-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(500 mg, 1.36 mmol) obtained in Example 343, 4-isopropylphenol (556 mg,4.08 mmol) and potassium carbonate (188 mg, 1.36 mmol) in pyridine (16mL) was stirred at 140° C. under argon atmosphere for 1 hour. Copperiodide (259 mg, 1.36 mmol) was added to the reaction solution and themixture was stirred at 140° C. for 60 hours. Water was added to thereaction solution and the product was extracted with ethyl acetate. Thecombined organic layers were washed with 1 N hydrochloric acid and anaqueous saturated sodium hydrogen carbonate solution, dried overanhydrous sodium sulfate, filtered, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:4) and Gilson HPLC to obtain 230mg (yield: 40%) of the title compound. Melting point: 148-149° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.14 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.42 (6H, s),2.00 (3H, s), 2.11 (3H, s), 2.27 (2H, s), 2.84 (1H, septet, J=6.9 Hz),2.97 (2H, s), 6.56 (1H, br s), 6.77 (2H, d, J=8.7 Hz), 7.06 (2H, d,J=8.7 Hz).

EXAMPLE 3453,3-Dimethyl-N-(2,2,4,6-tetramethyl-7-(4-methylphenoxy)-2,3-dihydro-1-benzofuran-5-yl)butanamide

UsingN-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 343 and 4-methylphenol, the title compound wassynthesized in the same manner as in Example 344. Yield: 19%. Meltingpoint: 182-184° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.35 (3H, s), 1.48 (3H, s), 1.98 (3H, brs), 2.08 (3H, s), 2.25 (2H, s), 2.86-2.97 (2H, m), 5.28 (1H, br s), 6.14(1H, d, J=3.84 Hz), 6.66 (1H, br s), 7.11-7.17 (2H, m), 7.54-7.59 (1H,m), 8.51 (1H, d, J=5.0 Hz).

EXAMPLE 346N-(3-Hydroxy-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Reference Example 330, the title compound was synthesized inthe same manner as in Example 234. Yield: 81%. Melting point: 244-245°C. (THF-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.33 (3H, s),1.51 (3H, s), 2.09 (3H, s), 2.26 (5H, m), 2.84 (1H, septet, J=6.9 Hz),3.91 (2H, d, J=15.0 Hz), 4.76 (1H, d, J=8.7 Hz), 6.53 (1H, br s), 7.07(4H, s), 1H unidentified.

EXAMPLE 347N-(3-Hydroxy-7-(4-isopropylbenzyl)-2,2,3,4,6-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Reference Example 330 and methylmagnesium bromide, the titlecompound was synthesized in the same manner as in Example 239. Yield:92%. Melting point: 170-171° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.20 (6H, d, J=6.9 Hz), 1.33 (3H, s),1.41 (3H, s), 1.44 (3H, s), 2.08 (3H, s), 2.27 (2H, s), 2.32 (3H, s),2.83 (1H, septet, J=6.9 Hz), 3.91 (2H, br), 6.49 (1H, br s), 7.06 (4H,s), 1H unidentified.

EXAMPLE 348N-(3-(4-Isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1′-cyclopentan)-5-yl)-3,3-dimethylbutanamide

Using3-(4-isopropylphenyl)-4,6,7-trimethyl-3H-spiro(1-benzofuran-2,1′-cyclopentane)-5-amineobtained in Reference Example 325, the title compound was synthesized inthe same manner as in Example 1. Yield: 57%. Melting point: 209-210° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.06-1.38 (16H, m), 1.50-1.92 (9H, m), 1.99-2.08 (1H,m), 2.14 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.84 (1H, septet, J=6.9Hz), 4.16 (1H, s), 6.48 (1H, br s), 6.88 (2H, d, J=8.1 Hz), 7.05 (2H, d,J=8.1 Hz).

EXAMPLE 349N-((cis)-3-(4-Isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(cis)-3-(4-isopropylphenyl)-2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-aminehydrochloride obtained in Reference Example 351 and tert-butylacetylchloride, the title compound was synthesized in the same manner as inExample 316. Yield: 83%. Melting point: 94-95° C. (hexane).

¹H-NMR (CDCl₃) δ: 1.03 (3H, d, J=7.0 Hz), 1.09 (9H, s), 1.22 (6H, d,J=7.0 Hz), 2.15 (3H, s), 2.19 (2H, s), 2.21 (3H, s), 2.86 (1H, septet,J=7.0 Hz), 4.31 (1H, d, J=8.0 Hz), 4.96-5.05 (1H, m), 6.72 (1H, s), 6.89(2H, d, J=8.0 Hz), 7.00 (1H, s), 7.11 (2H, d, J=8.0 Hz).

EXAMPLE 350(cis)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine

Using(cis)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuranobtained in Reference Example 352,(cis)-5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuranwas synthesized in the same manner as in Reference Example 23. Using thecompound,(cis)-N-benzyl-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-aminewas synthesized in the same manner as in Reference Example 24. Using thecompound, the title compound was synthesized in the same manner as inReference Example 30. Yield: 83%. Melting point: 91-92° C. (hexane).

¹H-NMR (200 MHz, CDCl₃) δ: 1.06 (3H, d, J=7.0 Hz), 1.21 (6H, d, J=7.0Hz), 1.84 (3H, s), 2.12 (3H, s), 2.21 (3H, s), 2.85 (1H, septet, J=7.0Hz), 3.25 (2H, br s), 4.29 (1H, d, J=8.0 Hz), 4.83-4.96 (1H, m), 6.83(2H, d, J=8.0 Hz), 7.07 (2H, d, J=8.0 Hz).

EXAMPLE 351N-((trans)-3-(4-Isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using 3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran obtained inReference Example 347, a mixture of cis isomer and trans isomer (3:2) of3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran wassynthesized in the same manner as in Reference Example 199. Using themixture as it is as the compound, a mixture of cis isomer and transisomer of5-bromo-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuranwas obtained in the same manner as in Reference Example 23. Using thecompound, a mixture of cis isomer and trans isomer ofN-benzyl-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)aminewas obtained in the same manner as in Reference Example 24. Using thecompound,(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)aminewas synthesized in the same manner as in Reference Example 30. Using thecompound and tert-butylacetyl chloride, a mixture of cis isomer andtrans isomer ofN-(3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamidewas obtained in the same manner as in Example 1. The compound waspurified by silica gel column chromatography (ethyl acetate:hexane=1:4)to synthesize the title compound. Yield: 18%. Melting point: 143-144° C.(hexane)

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=7.0 Hz), 1.46 (3H, d,J=6.0 Hz), 1.76 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.86(1H, septet, J=7.0 Hz), 4.08 (1H, d, J=6.0 Hz), 4.58-4.67 (1H, m), 6.48(1H, s), 7.05 (2H, d, J=8.0 Hz), 7.13 (2H, d, J=8.0 Hz).

EXAMPLE 352N-(7-(Hydroxy(pyridin-2-yl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

To a solution of 2-bromopyridine (553 mg, 3.5 mmol) in diethyl ether(3.0 mL) was added dropwise at −70° C. under argon atmospheren-butyllithium (1.6 M, hexane solution, 2.13 mL, 3.4 mmol) and themixture was stirred for 30 minutes. To the reaction solution was addeddropwise at −70° C. a solution ofN-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide(317 mg, 1.0 mmol) obtained in Example 340 in THF (4.0 mL) and themixture was stirred for 30 minutes, and then warmed to room temperature.Water was added to the reaction solution and the product was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate, and then concentrated under reducedpressure. The residue was purified by basic silica gel columnchromatography (ethyl acetate:hexane=1:10), and then by silica gelcolumn chromatography (ethyl acetate:hexane=1:1) to obtain 270 mg(yield: 68%) of the title compound. Melting point: 176-177° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.35 (3H, s), 1.48 (3H, s), 1.98 (3H, brs), 2.08 (3H, s), 2.25 (2H, s), 2.86-2.97 (2H, m), 5.28 (1H, br s), 6.14(1H, d, J=3.84 Hz), 6.66 (1H, br s), 7.11-7.17 (2H, m), 7.54-7.59 (1H,m), 8.51 (1H, d, J=5.0 Hz).

EXAMPLE 353N-(7-(1-Hydroxy-2-(4-isopropylphenyl)ethyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 340 and 4-isopropylbenzyl chloride, the titlecompound was synthesized in the same manner as in Example 341. Yield:92%. Amorphous substance.

¹H-NMR (CDCl₃) δ: 1.12 and 1.17 (9H, s x 2), 1.20-1.25 (6H, m), 1.45 and1.48 (6H, s x 2), 1.88 (3H, s), 2.05 and 2.07 (3H, s x 2), 2.24 and 2.25(2H, s x 2), 2.79-3.11 (5H, m), 3.76 (1H, br d, J=16.0 Hz), 4.87-5.00(1H, m), 6.69 (1H, br s), 7.03-7.13 (4H, m).

EXAMPLE 354N-(7-(2-(4-Isopropylphenyl)ethyl))-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-(1-hydroxy-2-(4-isopropylphenyl)ethyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 353, the title compound was synthesized in the samemanner as in Example 271. Yield: 64%. Melting point: 144-145° C.(hexane-ethyl acetate).

¹H-NMR (CDCl₃) δ: 1.15 (9H, s), 1.23 (3H, s), 1.25 (3H, s), 1.43 (6H,s), 2.07 (3H, s), 2.13 (3H, s), 2.29 (2H, s), 2.69-2.88 (5H, m), 2.92(2H, br s), 6.51 (1H, br s), 7.15 (4H, s).

EXAMPLE 355N-(7-(1-Hydroxy(phenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-butanamideobtained in Example 340 and phenylmagnesium bromide, the title compoundwas synthesized in the same manner as in Example 239. The yield wasquantitative. Amorphous substance.

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.38 (3H, s), 1.49 (3H, s), 2.07 (3H,s), 2.10 (3H, s), 2.27 (2H, s), 2.92 (2H, s), 4.24 (1H, br d, J=10.0Hz), 5.91 (1H, d, J=10.0 Hz), 6.68 (1H, br s), 7.20-7.36 (5H, m).

EXAMPLE 356N-((7-Benzyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

UsingN-(7-(1-hydroxy(phenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 355, the title compound was synthesized in the samemanner as in Example 271. Yield: 74%. Melting point: 129-130° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.46 (6H, s), 2.04 (3H, s), 2.08 (3H,s), 2.25 (2H, s), 2.96 (2H, br s), 3.93 (2H, br s), 6.49 (1H, br s),7.10-7.20 (5H, m).

EXAMPLE 3573,3-Dimethyl-N-(2,2,4,6-tetramethyl-7-(2-methylbenzyl)-2,3-dihydro-1-benzofuran-5-yl)butanamide

UsingN-(7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethyl-butanamideobtained in Example 340 and 2-methylphenylmagnesium bromide,N-(7-(hydroxy(2-methylphenyl)methyl)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamidewas synthesized in the same manner as in Example 239. Using thecompound, the title compound was synthesized in the same manner as inExample 271. Yield: 24%. Melting point: 175-176° C. (ethylacetate-hexane).

¹H-NMR (CDCl₃) δ: 1.13 (9H, s), 1.41 (6H, s), 1.94 (3H, s), 2.12 (3H,s), 2.27 (2H, s), 2.38 (3H, s), 2.96 (2H, br s), 3.85 (2H, br s), 6.54(1H, br s), 6.76 (1H, d, J=7.0 Hz), 6.98-7.14 (3H, m)

EXAMPLE 358N-((3R)-7-(2-Furyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(−)-N-((3R)-7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 51 and 2-furyl(diphenyl)methanol, the title compoundwas obtained in the same manner as in Example 107. Yield: 6%. Meltingpoint: 214-217° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.12 (9H, s), 1.22 (6H, d, J=6.9 Hz), 1.89 (3H, s),2.27 (5H, s), 2.86 (1H, septet, J=6.9 Hz), 4.46 (1H, dd, J=4.9, 8.6 Hz),4.56 (1H, dd, J=4.9, 9.1 Hz), 4.87 (1H, dd, J=8.6, 9.1 Hz), 6.51 (1H,dd, J=1.6, 3.3 Hz), 6.53 (1H, s), 6.58 (1H, d, J=3.3 Hz), 7.07 (2H, d,J=8.2 Hz), 7.13 (2H, d, J=8.2 Hz), 7.53 (1H, d, J=1.6 Hz).

EXAMPLE 359N-((3R)-7-Benzoyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide

Using(+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideobtained in Example 37 and benzoyl chloride, the title compound wasobtained in the same manner as in Example 38.

Yield: 74%. Melting point: 205-206° C. (ethyl acetate-hexane).

¹H-NMR (CDCl₃) δ: 1.11 (9H, s), 1.23 (6H, d, J=6.9 Hz), 1.93 (3H, s),2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J=6.9 Hz), 4.34 (1H, dd,J=4.9, 8.6 Hz), 4.54 (1H, dd, J=4.9, 9.1 Hz), 4.77 (1H, dd, J=8.6, 9.1Hz), 6.59 (1H, s), 7.06 (2H, d, J=7.9 Hz), 7.14 (2H, d, J=7.9 Hz), 7.46(2H, dd, J=7.4, 7.7 Hz), 7.57 (1H, t, J=7.4 Hz), 7.92 (2H, d, J=7.7 Hz).

The structures of the compounds of Examples are shown in the followingtables 1 to 7.

TABLE 1

Example X R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) comment 1 O H 4-iPrPh HMe t-BuCH₂CONH Me Me 2 O H 4-iPrPh H H t-BuCH₂CONH Me Me 3 O H 4-iPrPh HMe t-BuCH₂CONH Me H 4 O H 4-iPrPh H H t-BuCH₂CONH H H 5 O H 4-iPrPh MeMe t-BuCH₂CONH Me Me 6 O H 4-iPrPh Me H t-BuCH₂CONH Me Me 7 O H 4-iPrPhH Me t-BuCH₂CONH Me Me (R)-(+) form 8 O H 4-iPrPh H Me t-BuCH₂CONH Me Me(S)-(−) form 9 O H 4-iPrPh H Me CH₃CH₂CONH Me Me 10 O H 4-iPrPh H MeCH₃(CH₂)₂CONH Me Me 11 O H 4-iPrPh H Me CH₃(CH₂)₃CONH Me Me 12 O H4-iPrPh H Me 4-MeOPhCH₂CONH Me Me 13 O H 4-iPrPh H Me 4-MeOPh(CH₂)₂CONHMe Me 14 O H 4-iPrPh H Me t-BuNHCONH Me Me 15 O H 4-iPrPh H MeEtOC(O)CONH Me Me 16 O H 4-iPrPh H Me t-BuC(O)CONH Me Me 17 O H 4-iPrPhH Me EtC(O)CONH Me Me 18 O H 4-iPrPh H Me EtCH(OH)CONH Me Me 19 O H4-iPrPh H Me t-BuCH(OH)CONH Me Me 20 O H 4-iPrPh H Me t-BuCH₂CONH Me CHO21 O H 4-iPrPh H Me t-BuCH₂CONH Me CH₂OH 22 O H 4-iPrPh H Me t-BuCH₂CONHMe MeCH(OH) 23 O H 4-iPrPh H Me t-BuCH₂CONH Me Et 24 O H 4-iPrPh H Met-BuCH₂CON(Me) Me Me less polar 25 O H 4-iPrPh H Me t-BuCH₂CON(Me) Me Memore polar 26 O H 4-iPrPh H Me t-BuCH₂CONH Me CH₂pyrrolidine 27 O H4-iPrPh H Me t-BuCH₂CONH Me CH₂NMe₂ 28 O H 4-iPrPh H Me t-BuCH₂CONH MeMeCH(OH) less polar 29 O H 4-iPrPh H Me t-BuCH₂CONH Me MeCH(OH) morepolar 30 O H 4-iPrPh H Me t-BuCH₂CONH Me EtCH(OH) less polar 31 O H4-iPrPh H Me t-BuCH₂CONH Me EtCH(OH) more polar 32 O H 4-iPrPh H Met-BuCH₂CONH Me Ac 33 O H 4-iPrPh H Me t-BuCH₂CONH Me Me₂C(OH) 34 O H4-iPrPh H Me t-BuCH₂CONH Me n-Pr 35 O H 4-iPrPh H Me t-BuCH₂CONH Me Br36 O H 4-iPrPh H Me t-BuCH₂CONH Me MeO 37 O H 4-iPrPh H Me t-BuCH₂CONHMe H (R)-(+) form 38 O H 4-iPiPh H Me t-BuCH₂CONH Me Ac (R)-(+) form 39O H 4-iPrPh H Me t-BuCH₂CONH Me CHO (R)-(−) form 40 O H 4-iPrPh H Met-BuCH₂CONH Me MeCH(OH) less polar (R)-(+) form 41 O H 4-iPrPh H Met-BuCH₂CONH Me MeCH(OH) more polar (R)-(+) form 42 O H 4-iPrPh H Met-BuCH₂CONH Me Et (R)-(+) form 43 O H 4-iPrPh H Me t-BuCH₂CONH MeEtCH(OH) less polar (R)-(+) form 44 O H 4-iPrPh H Me t-BuCH₂CONH MeEtCH(OH) more polar (R)-(+) form 45 O H 4-iPrPh H Me t-BuCH₂CONH Me n-Pr(R)-(+) form 46 O H 4-iPrPh H Me t-BuCH₂CONH Me Me₂C(OH) (R)-(+) form 47O H 4-iPrPh H Me t-BuNHCONH Me H (R)-(+) form 48 O H 4-iPrPh H Met-BuNHCONH Me CHO (R)-(−) form 49 O H 4-iPrPh H Me t-BuNHCONH Me CH₂OH(R)-(+) form 50 O H 4-iPrPh H Me t-BuNHCONH Me Me (R)-(+) form 51 O H4-iPrPh H Me t-BuCH₂CONH Me Br (R)-(−) form 52 O H 4-iPrPh H Met-BuCH₂CONH Me MeO (R)-(+) form

TABLE 2

Example X R¹ R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) comment 53 O H H4-iPr-Ph H Me MeSO₂NH Me Me 54 O H H 4-iPr-Ph H Me nBuSO₂NH Me Me 55 O HH 4-iPr-Ph H Me CF₃(CH₂)₃SO₂NH Me Me 56 O H H 4-iPr-Ph H Me EtSO₂NH MeMe 57 O H H 4-iPr-Ph H Me nPrSO₂NH Me Me 58 O H H 4-iPr-Ph H Me OHCNH MeH 59 O H H 4-iPr-Ph H Me OHCNH Me Br 60 O H H 4-iPr-Ph H Me OHCNH Me CHO61 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me (CH₂)₂CO₂Et 62 O H H 4-iPr-Ph H Met-BuCH₂CONH Me (CH₂)₃OH 63 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me Me 64 O HH 4-iPr-Ph H Me t-BuCH₂CONH H Me 65 O H H 4-iPr-Ph H Me Me t-BuCH₂CONHMe 66 O H H 4-iPr-Ph H Me Me Me t-BuCH₂CONH 67 O H H 4-iPr-Ph H MeBzO(CH₂)₃CONH Me Me 68 O H H 4-iPr-Ph H Me t-BuCH₂CONH CH═CH—CH═CH 69 OH H 4-iPr-Ph H Me t-BuCH₂CONH (CH₂)₄ 70 O H H 4-iPr-Ph H Me t-BuCH₂CONH(CH₂)₃ 71 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me H 72 O H H 3-MeO-Ph H Met-BuCH₂CONH Me Me s-form 73 O H H 3-(1,3-dioxolan-2-yl)-Ph H Met-BuCH₂CONH Me Me 74 O H H 4-iPr-2-MeO-Ph H Me t-BuCH₂CONH Me Me 75 O HH Ph H Me t-BuCH₂CONH Me Me 76 O H H 4-Me-Ph H Me t-BuCH₂CONH Me Me 77 OH H biphenyl H Me t-BuCH₂CONH Me Me 78 O H H 5-Me-2-Py H Me t-BuCH₂CONHMe Me 79 O H H 4-Et-Ph H Me t-BuCH₂CONH Me Me 80 O H H 4-iBu-Ph H Met-BuCH₂CONH Me Me 81 O H H 4-cHex-Ph H Me t-BuCH₂CONH Me Me 82 O H H4-(1,3-dioxolan-2-yl)-Ph H Me t-BuCH₂CONH Me Me 83 O H H 4-iPr-Ph H Met-BuCH₂CONH Me CH═CH₂ 84 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me CH(OH)CH₂OH85 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me (CH₂)₂OH 86 O H H 4-iPr-Ph H Met-BuCH₂CONH Me EtCO 87 O H H 4-iPr-Ph H Me t-BuCH₂CONH Br Me 88 O H H4-iPr-Ph H OMe t-BuCH₂CONH Me Me 89 O H H 4-iPr-Ph H Me t-BuCH₂CONH OMeMe 90 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me CH(OH)(CH₂)₂CH₃ 91 O H H4-iPr-Ph H Me t-BuCH₂CONH Me CH(OH)(CH₂)₂CH₃ 92 O H H 4-iPr-Ph H Met-BuCH₂CONH Me nBu less polar 93 O H H 4-iPr-Ph H Me HO(CH₂)₃CONH Me Memore polar 94 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me CH(OH)Ph 95 O H H4-iPr-Ph H Me t-BuCH₂CONH Me CH(OH)(4-iPr-Ph) 96 O H H 4-iPr-Ph H Met-BuCH₂CONH Me CH₂Ph 97 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me CH₂(4-iPr-Ph)98 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me. COOH 99 O H H 4-iPr-Ph H Met-BuCH₂CONH Me CN 100 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me Ac 101 O H H4-iPr-Ph H Me t-BuCH₂CONH Me Ph 102 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me6-MeO-3-Py s-form 103 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 4-MeO-Ph 104 OH H 4-iPr-Ph H Me t-BuCH₂CONH Me 6-F-3-Py

TABLE 3

Example X R¹ R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) comment 105 O H H4-iPr-Ph H Me t-BuCH₂CONH Me 3-MeO-Ph 106 O H H 4-iPr-Ph H Met-BuCH₂CONH Ph Me 107 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 3-(AcNH)-Ph 108O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 3-F-Ph 109 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 3-NO₂-Ph 110 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me3-(CO₂Me)-Ph 111 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 3-AcPh 112 O H H4-iPr-Ph H Me t-BuCH₂CONH Me 3-(CO₃Et)-Ph 113 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 4-Me-Ph (R)-(+) form 114 O H H 4-iPr-Ph H Me t-BuCH₂CONHMe 3-Py 115 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 4-Py 116 O H H 4-iPr-Ph HMe t-BuCH₂CONH Me B(OH)₂ 117 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 2-Py 118O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 5-Me-2-Py 119 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 6-NH₂-2-Py 120 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me3-(Me₂N)-Ph 121 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 6-(AcNH)-2-Py 122 O HH 4-iPr-Ph H Me t-BuCH₂CONH Me 3-NH₂-Ph 123 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 3-(EtCONH)-Ph 124 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me5-pyrimidinyl 125 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 2-thiazoiyl 126 O HH 4-iPr-Ph H Me t-BuCH₂CONH Me 3-thienyl 127 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 4-imidazolyl 128 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me3-furyl 129 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 2-pyrrolyl 130 O H H4-iPr-Ph H Me t-BuCH₂CONH Me 2-thienyl 131 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 5-Ac-2-thienyl 132 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me5-Ac-3-thienyl 133 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 4-Me-2-thiazolyl134 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me OH 135 O H H 4-iPr-Ph H Met-BuCH₂CONH Me OH 136 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me EtO 137 O H H4-iPr-Ph H Me t-BuOCONH Me Me 138 O H H 4-iPr-Ph H Me Cl₃CCH₂OCONH Me Me139 O H H 4-iPr-Ph H Me Cl₃CCH₂OCONH Me Et 140 O H H 4-iPr-Ph H MeCl₃CCH₂OCONH Me OMe 141 O H H 4-iPr-Ph H Me Cl₃CCH₂OCONH Me (CH₂)₃OH 142O H H 4-iPr-Ph H Me Cl₃CCH₂OCONH Me Ph 143 O H H 4-iPr-Ph H Me C₄H₈NCONHMe Me less polor 144 O H H 4-iPr-Ph H Me Et₂NCONH Me Me more polor 145 OH H 4-iPr-Ph H Me HO(CH₂)₃NHCONH Me Me 146 O H H 4-iPr-Ph H MeMeO(CH₂)₃NHCONH Me Me 147 O H H 4-iPr-Ph H Me Me₂N(CH₂)₂NHCONH Me Me 148O H H 4-iPr-Ph H Me HO(CH₂)₃NHCONH Me Me 149 O H H 4-iPr-Ph H MeHO(CH₂)₃NHCONH Me OMe 150 O H H 4-iPr-Ph H Me HO(CH₂)₃NHCONH Me (CH₂)₃OH151 O H H 4-iPr-Ph H Me nPrNHCONH Me Me 152 O H H 4-iPr-Ph H MeHO(CH₂)₃NHCONH Me Ph 153 O H H 4-iPr-Ph H Me HO(CH₂)₃NHCONH Me Ph 154 OH H 4-iPr-Ph H Me HO(CH₂)₃NHCONH Me Me 155 O H H 4-iPr-Ph H MeHO(CH₂)₃NHCONH Me Me 156 O H H 4-iPr-Ph H Me HOCH₂C(Me)₃NHCONH Me Me

TABLE 4

Example X R¹ R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) Note 157 O H H4-iPr-Ph H Me HOCH₂C(Me)₂NHCONH Me Ph 158 O H H 4-iPr-Ph H MeHOCH₂C(Me)₂CH₂NHCONH Me Me 159 O H H 4-iPr-Ph H Me HOCH₂C(Me)₂CH₂NHCONHMe Ph 160 O H H 4-iPr-Ph H Me HOCH(Me)CH₂NHCONH Me Ph 161 S H H 4-iPr-PhH Me t-BuCH₂CONH Me H 162 S H H 4-iPr-Ph H Me t-BuCH₂CONH Me Br 163 S HH 4-iPr-Ph H Me t-BuCH₂CONH Me CHO 164 S H H 4-iPr-Ph H Me t-BuCH₂CONHMe Et 165 S H H 4-iPr-Ph H Me t-BuCH₂CONH Me nPr 166 S H H 4-iPr-Ph H Met-BuCH₂CONH Me Ac 167 S(O) H H 4-iPr-Ph H Me t-BuCH₂CONH Me Et 168 S(O)H H 4-iPr-Ph H Me t-BuCH₂CONH Me Ac 169 S(O) H H 4-iPr-Ph H Met-BuCH₂CONH Me Ac 170 SO2 H H 4-iPr-Ph H Me t-BuCH₂CONH Me Br 171 SO2 HH 4-iPr-Ph H Me t-BuCH₂CONH Me Ac 172 SO2 H H 4-iPr-Ph H Me t-BuCH₂CONHMe Et 173 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me Me 174 O H H 4-iPr-Ph H Met-BuCH₂CONH Me Me 175 O H H 4-MeCH(OH)-Ph H Me t-BuCH₂CONH Me Me 176 O HH 4-AcPh H Me t-BuCH₂CONH Me Me 177 O H H 3-EtOC(═O)CH═CHPh H Met-BuCH₂CONH Me Me 178 O H H 4-EtOC(═O)CH═CHPh H Me t-BuCH₂CONH Me Me 179O H H 4-EtOC(═O)CH═C(Me)Ph H Me t-BuCH₂CONH Me Me 180 O H H3-EtOC(═O)(CH₂)₂Ph H Me t-BuCH₂CONH Me Me 181 O H H 3-EtOC(═O)(CH₂)₂Ph HMe t-BuCH₂CONH Me Me 182 O H H 4-EtOC(═O)CH₃CH(Me)Ph H Me t-BuCH₂CONH MeMe 183 O H H 4-Ac-3-MeOPh H Me t-BuCH₂CONH Me Me 184 O H H4-(H₂C═C(Me))-3-MeOPh H Me t-BuCH₂CONH Me Me 185 O H H 4-iPr-3-MeOPh HMe t-BuCH₂CONH Me Me 186 O H H 4-iPr-3-(HO)Ph H Me t-BuCH₂CONH Me Me 187O H H 4-iPr-2-(HO)Ph H Me t-BuCH₂CONH Me Me 188 O H H4-iPr-3-(EtOC(O)CH₂O)Ph H Me t-BuCH₂CONH Me Me 189 O H H4-iPr-2-(MeC(O)CH₂O)Ph H Me t-BuCH₂CONH Me Me 190 O H H4-iPr-2-(EtOC(O)CH₂O)Ph H Me t-BuCH₂CONH Me Me 191 O H H4-iPr-3-(MeO(CH₂)₂O)Ph H Me t-BuCH₂CONH Me Me 192 O H H4-iPr-2-(MeO(CH₂)₂O)Ph H Me t-BuCH₂CONH Me Me 193 O H H4-iPr-3-(HO(CH₂)₂O)Ph H Me t-BuCH₂CONH Me Me 194 O H H 3-HO(CH₂)₃Ph H Met-BuCH₂CONH Me Me 195 O H H 4-HO(CH₂)₃Ph H Me t-BuCH₂CONH Me Me 196 O HH 4-HO(CH₂)₂CH(Me)Ph H Me t-BuCH₂CONH Me Me 197 O H H4-iPr-2-(HO(CH₂)₂O)Ph H Me t-BuCH₂CONH Me Me 198 O H H4-HOC(═O)CH₂CH(Me)Ph H Me t-BuCH₂CONH Me Me 199 O H H 4-Me₂C(OH)Ph H Met-BuCH₂CONH Me Me 200 O H H 4-iPr-Ph H Me CF₃(CH₂)₂CONH Me Me 201 O H N4-iPr-Ph H Me Me₂NCH₂CONH Me Me 202 O H H 4-iPr-Ph H Me t-BuCONH Me Me203 O H H 4-iPr-Ph H Me NHCHO Me Ac 204 O H H 4-iPr-Ph H Me t-BuNHCONHMe Ac 205 O H H 4-iPr-Ph H Me (c-Hex)NHCONH Me Me 206 O H H 4-iPr-Ph HMe Cl₃CCH₂OCONH Me Ac 207 O H H 4-iPr-Ph H Me HO(CH₂)₃NHCONH Me Ac 208 OH H 4-iPr-Ph H Me t-BuNHCONH Me CH(OH)Me

TABLE 5

Example X R¹ R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) Note 209 O H H4-iPr-Ph H Me t-BuNHCONH Me Me 210 O H H 4-iPr-Ph H Me HO(CH₂)₂NHCONH MeAc 211 O H H 4-iPr-Ph H Me t-BuCH₂CONH Me 3-(1-pyrrolidinyl)Ph 212 O H H4-iPr-Ph H Me t-BuCH₂CONH Me (4-Me₂N)Ph 213 O H H 4-iPr-Ph H Met-BuCH₂CONH Me 6-Me₂N-3-Py 214 O H H Me H Me t-BuCH₂CONH Me 4-iPr-Bz 215O H H Et H Me t-BuCH₂CONH Me 4-iPr-Bz 216 O H H n-Pr H Me t-BuCH₂CONH Me4-iPr-Bz 217 O H H i-Pr H Me t-BuCH₂CONH Me 4-iPr-Bz 218 O H H H H Men-PrCONH Me 4-iPr-Bz 219 O H H H H Me EtCONH Me 4-iPr-Bz 220 O H H H HMe n-BuCONH Me 4-iPr-Bz 221 O H H H H Me t-BuOCONH Me H 222 O H H H H Met-BuOCONH Me Br 223 O H H H H Me t-BuOCONH Me C(OH)(Me)(4-iPr-Ph) 224 OH H H H Me n-PrCONH Me CH(Me)(4-iPr-Ph) 225 O H H H H Me t-BuCH₂CONH MeCH(Me)(4-iPr-Ph) 226 O H H H H Me t-BuCH₂CONH Me C(═CH₂)(4-iPr-Ph) 227 OH H H H Me t-BuNHCONH Me 4-iPr-Bz 228 O H H H H Me HO(CH₂)₂NHCONH Me4-iPr-Bz 229 O H H H H Me t-BuCH₂CONH Me 4-iPr-Bz 230 O H H CH₂OH H Met-BuCH₂CONH Me 4-iPr-Bz 231 O H H Ph H Me t-BuCH₂CONH Me H 232 O H H PhH Me t-BuCH₂CONH Me CHO 233 O H H Ph H Me t-BuCH₂CONH Me 4-iPr-Bz 234 OMe Me OH H Me t-BuCH₂CONH Me Me 235 O Me Me OH H H t-BuCH₂CONH Me Me 236O Me Me OH H Me t-BuOCONH Me Br 237 O Me Me H H Me t-BuOCONH Me H 238 OMe Me H H Me t-BuOCONH Me Br 239 O Me Me 3-Me-Ph OH H t-BuCH₂CONH Me Me240 O Me Me (CH₂)₂Ph OH H t-BuCH₂CONH Me Me 241 O Me Me 2-CF₃O-Ph OH Ht-BuCH₂CONH Me Me 242 O Me Me 2-Me-Ph OH H t-BuCH₂CONH Me Me 243 O Me MePh OH H t-BuCH₂CONH Me Me 244 O Me Me 2-naph OH H t-BuCH₂CONH Me Me 245O Me Me 3-iPr-Ph OH H t-BuCH₂CONH Me Me 246 O Me Me 2-MeO-Ph OH Ht-BuCH₂CONH Me Me 247 O Me Me 4-iPr-Ph OH H i-BuCH₂CONH Me Me 248 O MeMe 2-thienyl OH H t-BuCH₂CONH Me Me 249 O Me Me Bz OH H t-BuCH₂CONH MeMe 250 O Me Me 4-iPr-Bz OH H t-BuCH₂CONH Me Me 251 O Me Me n-Bu OH Ht-BuCH₂CONH Me Me 252 O Me Me 2-furyl OH H t-BuCH₂CONH Me Me 253 O Me Me2,4-MeO-Ph OH H t-BuCH₂CONH Me Me 254 O Me Me 4-Br-Ph OH H t-BuCH₂CONHMe Me 255 O Me Me 4-MeO-Ph OH H t-BuCH₂CONH Me Me 256 O Me Me c-Hex OHMe t-BuCH₂CONH Me Me 257 O Me Me 2-Py OH Me t-BuCH₂CONH Me Me 258 O MeMe 4-MeO-Ph OH Me t-BuCH₂CONH Me Me 259 O Me Me 3-MeO-Ph OH Met-BuCH₂CONH Me Me 260 O Me Me 4-iPr-Ph OH Me Me Me t-BuCH₂CONH

TABLE 6

Example X R¹ R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) Note 261 O Me Me4-Me-Ph OH Me t-BuOCONH Me Me 262 O Me Me 4-iPr-Ph OH Me t-BuOCONH Me Me263 O Me Me 2-naph OH Me t-BuOCONH Me Me 264 O Me Me 3-CHO-Ph OH Ht-BuCH₂CONH Me Me 265 O Me Me 3-(CH₂OH)-Ph OH H t-BuCH₂CONH Me Me 266 OMe Me 3-(CH(Me)OH)-Ph OH H t-BuCH₂CONH Me Me 267 O Me Me 4-Me-Ph OH Met-BuCH₂CONH Me Me 268 O Me Me 2-naph OH Me t-BuCH₂CONH Me H 269 O Me Me2-naph OH Me i-BuCH₂CONH Me Me 270 O Me Me 2-naph OH Me t-BuNHCONH Me Me271 O Me Me 2-Me-Ph H H t-BuCH₂CONH Me Me 272 O Me Me 3-Me-Ph H Ht-BuCH₂CONH Me Me 273 O Me Me 3-iPr-Ph H H t-BuCH₂CONH Me Me 274 O Me MePh H H t-BuCH₂CONH Me Me 275 O Me Me 2-naph H H t-BuCH₂CONH Me Me 276 OMe Me 2-MeO-Ph H H t-BuCH₂CONH Me Me 277 O Me Me Bz H H t-BuCH₂CONH MeMe 278 O Me Me 4-iPr-Bz H H t-BuCH₂CONH Me Me 279 O Me Me 2-thienyl H Ht-BuCH₂CONH Me Me 280 O Me Me 2-CF₃O-Ph H H t-BuCH₂CONH Me Me 281 O MeMe n-Bu H H t-BuCH₂CONH Me Me 282 O Me Me 2-furyl H H t-BuCH₂CONH Me Me283 O Me Me (CH₂)₂Ph H H t-BuCH₂CONH Me Me 284 O Me Me 4-Br-Ph H Ht-BuCH₂CONH Me Me 285 O Me Me 4-MeO-Ph H H t-BuCH₂CONH Me Me 286 O Me Me2,4-MeO-Ph H H t-BuCH₂CONH Me Me 287 O Me Me c-Hex H Me t-BuCH₂CONH MeMe 288 O Me Me 2-Py H Me t-BuCH₂CONH Me Me 289 O Me Me 4-MeO-Ph H Met-BuCH₂CONH Me Me 290 O Me Me 3-MeO-Ph H Me t-BuCH₂CONH Me Me 291 O MeMe 4-iPr-Ph H Me Me Me t-BuCH₂CONH 292 O Me Me 4-CHO-Ph H H t-BuCH₂CONHMe Me 293 O Me Me 4-Ac-Ph H H t-BuCH₂CONH Me Me 294 O Me Me 3-(CH₂OH)-PhH H t-BuCH₂CONH Me Me 295 O Me Me 3-(CH(Me)OH)-Ph H H t-BuCH₂CONH Me Me296 O Me Me 2-iPr-Ph H H t-BuCH₂CONH Me Me 297 O Me Me 1-piperidyl H Met-BuCH₂CONH Me Me 298 O Me Me 1-pyrrolidinyl H H t-BuCH₂CONH Me Me 299 OMe Me NHPh H H t-BuCH₂CONH Me Me 300 O Me Me NH-(2-MeO-Ph) H Ht-BuCH₂CONH Me Me 301 O Me Me NH-(2-CF₃O-Ph) H H t-BuCH₂CONH Me Me 302 OMe Me 1-pyrrolidinyl H Me t-BuOCONH Me Br 303 O Me Me Me₂N H Met-BuOCONH Me Br 304 O Me Me 4-iPr-Ph H Me t-BuOCONH Me Me 305 O Me Me4-Me-Ph H Me t-BuOCONH Me Me 306 O Me Me H H Me t-BuCH₂CONH Me 4-iPr-Bz307 O Me Me 1-pyrrolidinyl H Me t-BuCH₂CONH Me 4-iPr-Bz 308 O Me Me Me₂NH Me t-BuCH₂CONH Me 4-iPr-Bz 309 O Me Me 4-Me-Ph H H t-BuCH₂CONH Me Me310 O Me Me 4-Me-Ph H Me n-PrCONH Me Me 311 O Me Me 4-Me-Ph H Men-BuCONH Me Me 312 O Me Me 4-Me-Ph H Me n-PenCONH Me Me

TABLE 7

Example X R¹ R² R³ R⁴ R^(7a) R^(7b) R^(7c) R^(7d) Note 313 O Me Me4-F-Ph H Me t-BuCH₂CONH Me Me 314 O Me Me Ph H Me t-BuCH₂CONH Me Me 315O Me Me 4-Bt-Ph H Me t-BuCH₂CONH Me Me 316 O Me Me 4-t-Bu-Ph H Met-BuCH₂CONH Me Me 317 O Me Me 4-iPr-Ph H H t-BuCH₂CONH Me Me 318 O Me Me4-iPr-Ph H Me t-BuCH₂CONH H Me 319 O Me Me 4-iPr-Ph H Me t-BuCH₂CONH MeH 320 O Me Me 4-iPr-Ph H H t-BuCH₂CONH H H 321 O Me Me 4-iPr-Ph H Hn-PrCONH H H 322 O Me Me 4-iPr-Ph H Me n-PrCONH Me Me 323 O Me Me4-iPr-Ph H Me n-BuCONH Me Me 324 O Me Me 4-iPr-Ph H Me t-BuCH₂CONH Me Me325 O Me Me 4-iPr-Ph H Me Me t-BuCH₂CONH Me 326 O Me Me Bz H Me Met-BuCH₂CONH H 327 O Me Me 4-iPr-Ph H H Me H t-BuCH₂CONH 328 O Me Me4-iPr-Ph H Me MeO Me t-BuCH₂CONH 329 O Me Me 4-iPr-Ph H H t-BuCH₂CON(Me)H H 330 O Me Me 4-iPr-Ph H Me (4-morpholinyl) Me Me (CH₂)₂CONH 331 O MeH H H Me t-BuOCONH Me H 332 O Me H H H Me t-BuOCONH Me Br 333 O Me H H HMe t-BuOCONH Me 4-iPr-Ph-CH(OH) 334 O Me H H H Me t-BuCH₂CONH Me4-iPr-Bz 335 O Me CH₂OH H H Me t-BuCH₂CONH Me 4-iPr-Bz 336 O Me CH₂I H HMe t-BuCH₂CONH Me 4-iPr-Bz 337 O Me CH₂ H H Me t-BuCH₂CONH Me 4-iPr-Bz(1-pyrrolidynyl) 338 O Me Me OH H Me t-BuCH₂CONH Me H 339 O Me Me H H Met-BuCH₂CONH Me H 340 O Me Me H H Me t-BuCH₂CONH Me CHO 341 O Me Me H HMe t-BuCH₂CONH Me 4-iPr-Ph-CH(OH) 342 O Me Me H H Me t-BuCH₂CONH Me4-iPr-Ph-CO 343 O Me Me H H Me t-BuCH₂CONH Me Br 344 O Me Me H H Met-BuCH₂CONH Me 4-iPr-Ph-O 345 O Me Me H H Me t-BuCH₂CONH Me 4-Me-Ph-O346 O Me Me OH H Me t-BuCH₂CONH Me 4-iPr-Bz 347 O Me Me OH Me Met-BuCH₂CONH Me 4-iPr-Bz 348 O (CH₂)₄ 4-iPr-Ph H Me t-BuCH₂CONH Me Me 349O Me H 4-iPr-Ph H H t-BuCH₂CONH Me Me cis-form 350 O Me H 4-iPr-Ph H Met-BuCH₂CONH Me Me cis-form 351 O Me H 4-iPr-Ph H Me t-BuCH₂CONH Me Metrans-form 352 O Me Me H H Me t-BuCH₂CONH Me (2-Py)CH(OH) 353 O Me Me HH Me t-BuCH₂CONH Me 4-iPr-Ph-CH₂CH(OH) 354 O Me Me H H Me t-BuCH₂CONH Me4-iPr-Ph-(CH₂)₂ 355 O Me Me H H Me t-BuCH₂CONH Me PHCH(OH) 356 O Me Me HH Me t-BuCH₂CONH Me Bz 357 O Me Me H H Me t-BuCH₂CONH Me 2-Me-Bz 358 OMe Me H H Me t-BuCH₂CONH Me 2-furyl R-form 359 O Me Me H H Met-BuCH₂CONH Me benzoyl R-form

FORMULATION EXAMPLE 1

The compound obtained in Example 1 was dissolved in a 30% (w/v)polyethylene glycol 400-containing saline to prepare a 0.01% solution ofthe compound. This solution was filtered through a bacterial filter anddispensed into vials by 10 mL, to provide an injectable solution forintravenous administration which contained 1 mg of the compound in eachvial.

FORMULATION EXAMPLE 2

The compound obtained in Example 1 was dissolved in a 5%cyclodextrin-containing saline to prepare a 0.1% solution of thecompound. This solution was filtered through a bacterial filter anddispensed into vials by 10 mL, to provide an injectable solution forintravenous administration which contained 10 mg of the compound in eachvial.

FORMULATION EXAMPLE 3

(1) The compound obtained in Example 1 50 mg (2) Lactose 34 mg (3) CornStarch 10.6 mg   (4) Corn Starch (paste)  5 mg (5) Magnesium stearate0.4 mg  (6) Calcium carboxylmethylcellulose 20 mg Total 120 mg 

According to a conventional method, the above-mentioned (1) to (6) aremixed and compressed by a tableting machine to produce tablets.

EXPERIMENTAL EXAMPLE 1 [³H]-CP55,940 Binding Assay with a Cell MembraneFraction Expressing Human CB1 and CB2 Receptor

[³H]-CP55940 binding inhibition assay was conducted by incubating a CHOcell membrane fraction expressing human CB1 receptor and the testcompound and 500 pM [³H]-CP55940 in reaction buffer (50 mM Tris-HCl(pH7.4), 5 mM MgCl₂, 2.5 mM EDTA and 0.5% BSA (fatty acid free)) at roomtemperature for 60 minutes. The reaction solution was filtered throughGF/C filter, washed with 30011 of washing buffer (50 mM Tris-HCl(pH7.4), 0.05% BSA (fatty acid free)) four times, and the radioactivityof the filter was measured with a Top Count scintillation counter(Packard). As results, the test compound has inhibited binding of[³H]-CP55940 to the membrane fraction dose-dependently.

The inhibitory activity of the test compound to [³H]-CP55940 binding wascalculated by percent on the basis that radioactivity is 100% when only500 pM [³H]-CP55940 was added, and 0% when 500 pM [³H]-CP55940 and 100nM CP55940 were added at the same time. Further, IC₅₀ value of the testcompound was calculated by analyzing concentrations and percents of thetest compound with PRISM 3.0 (Graphpad Software, Inc.).

The same assay was also conducted for a CHO cell membrane fractionexpressing human CB2 receptor, and the inhibitory activity to[³H]-CP55940 binding was calculated.

The results are shown in Table 8.

TABLE 8 Compound No. CB1 IC₅₀ value (nM) CB2 IC₅₀ value (nM) ReferenceExample 110 560 153 Reference Example 69 <10 212 Reference Example 55 55230 Reference Example 38 47 233 Reference Example 40 31 234 Example 1 20<10 Example 7 <10 <10 Example 9 79 11 Example 14 20 <10 Example 22 11<10 Example 23 <10 <10 Example 28 <10 <10 Example 29 <10 <10 Example 31<10 <10 Example 32 <10 <10 Example 33 14 <10 Example 34 <10 <10 Example35 <10 <10 Example 36 <10 <10

EXPERIMENTAL EXAMPLE 2 Body Temperature-lowering Action on Mouse

CB1 receptor agonistic activity of the compound of the present inventionin vivo was evaluated by investigating the effect on the bodytemperature of mouse after the drug was administered to the mouse. Inthis experiment, Jcl: ICR male mice (5 weeks old) were used. Aftermeasuring the rectal temperature with a thermometer (Physitemp BAT-12)that was connected to a probe for measuring body temperature, thecompound dissolved in 2.2% EtOH and 5% G2-β-cyclodextrin (solvent) wasadministered intraperitoneally. Solvent only was administered to thecontrol group. 30 minutes after administration, rectal temperature wasmeasured again. The experiment was conducted for 4 subjects per a group.

The test result was estimated as effective if the compound of thepresent invention lowered the body temperature substantially by 1° C. ormore when compared with the control group 30 minutes afteradministration of 1 mg/kg, i.p.

The results are shown in Table 9.

TABLE 9 Compound No. Test Results Example 1 Effective Example 7Effective Example 14 Effective Example 22 Effective Example 23 EffectiveExample 28 Effective Example 29 Effective Example 31 Effective Example32 Effective Example 33 Effective Example 34 Effective Example 35Effective Example 36 Effective

As shown in Table 9, the compound of the present invention exertedunusually body temperature-lowering action based on CB1 receptoragonistic activity at the low doses.

EXPERIMENTAL EXAMPLE 3 Effects of Reducing Cerebral Infarction inExperimental Model of Cerebral Infarction

In this experiment, Jcl: SD male rats (8 weeks old) were used. A canulafor infusion was inserted into the left common carotid vein underhalothane anesthesia.

Silicon-coated embolus was inserted into the left common carotid artery,to obstruct the middle cerebral artery (MCAO). 120 minutes after theobstruction, light anesthesia was conducted again with halothane, andreperfusion was done with the embolus removed. During MCAO, the ratswere observed for neural symptoms. The rats expressing typical neuralsymptoms were used in the experiment. The drug was dissolved in 2.2%EtOH and 5% G2-β-cyclodextrin (solvent). The test compound wasadministered intraperitoneally at three times as much as the minimumdose which was recognized to have body temperature lowering actionimmediately after the reperfusion, and further administered after 2, 4and 6 hours at the same dose. As used herein, the test compound wasselected from the compounds which had excellent activities inExperimental Example 1 and Experimental Example 2. The same amount ofthe solvent was administered to the control group. 2 days after treatingMCAO, the rats were decapitated, the brain was extracted and 6 frontalslices of 2 mm thickness was constructed under ice-cooling. Each slicewas dyed with a 1% TTC solution at 37° C. for 15 minutes, andphotographed with a digital camera. White-part area of each slice wasmeasured by image analyzing software (Photoshop (trademark)), and thevolume of the infarction was calculated by multiplying the area by thethickness of the slice. As a result, 30% or more of infarction volumewas recognized to be substantially reduced at the dose of 0.5 mg/kg.

As shown above, Compound (I), etc. have excellent modulating action oncannabinoid receptor function.

Further, Compound (I), etc. have protective action on cerebralinfarction, and, therefore, have medical actions such as treatingcerebrovascular disorders. Further, Compound (I), etc. are considered tohave very low toxicity and be well transferred into the brain.

INDUSTRIAL APPLICABILITY

As described above, an excellent cannabinoid receptor modulator which isuseful as a drug is provided according to the present invention.

1.(+)-N-((3R)-7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamideor a salt thereof. 2.(+)-N-((3R)-7-(1-hydroxyethyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide.